Download Conserved functions of retinoblastoma proteins: From purple retina

Plant Science 172 (2007) 671–683
www.elsevier.com/locate/plantsci
Review
Conserved functions of retinoblastoma proteins: From purple retina
to green plant cells
P. Miskolczi, Á. Lendvai, G.V. Horváth, A. Pettkó-Szandtner, D. Dudits *
Institute of Plant Biology, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, H-6701 Szeged, Hungary
Received 5 September 2006; received in revised form 19 December 2006; accepted 20 December 2006
Available online 3 January 2007
Abstract
The mammalian retinoblastoma susceptibility gene product, known as the first tumor suppressor protein (pRB), has a central role in the
regulation of the cell cycle, differentiation and apoptotic pathways of specific cell types. Discoveries in the past decade have shown that key
elements of the RB regulatory network also exist in higher plants which control a wide range of cellular functions, including cell division cycle and
differentiation. As we outline in this review, the plant RB-related proteins (RBRs) display amino acid sequence similarity and biochemical binding
properties analogous to their mammalian homologues and they can interact with E2F transcriptional factors, D-type cyclins and viral proteins. The
complex regulatory functions of the retinoblastoma proteins are discussed in detail by focusing in particular on the increasing amount of
information being produced about the role of these proteins in higher plants.
# 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Retinoblastoma; Pocket proteins; RBR; Cell cycle; Plant development
Contents
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conserved structure of the RB proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. RB activity depends on the phosphorylation level. . . . . . . . . . . . . . . . . . .
2.2. Active pRB level depends also on proteolysis . . . . . . . . . . . . . . . . . . . . .
2.3. Specific tools for the analysis of general functions: RB interacting partners
Broad functions of the retinoblastoma protein family in animals . . . . . . . . . . . . .
3.1. Retinoblastoma family and cell cycle regulation. . . . . . . . . . . . . . . . . . . .
3.2. Relevance to cancer and developmental defects . . . . . . . . . . . . . . . . . . . .
3.3. The role of pRB in the regulation of apoptosis . . . . . . . . . . . . . . . . . . . .
Plant retinoblastoma-related proteins (RBR) . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Retinoblastoma-related genes from plants . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Expression profiles of the plant RBR subfamily genes . . . . . . . . . . . . . . .
4.3. Increasing number of known interactors of plant RBR proteins . . . . . . . . .
4.4. RBR activity is regulated post-transcriptionally by phosphorylation . . . . . .
4.5. Plant RBR proteins play a fundamental role in G1/S transition . . . . . . . . .
4.6. Plant RBR functions in organogenesis . . . . . . . . . . . . . . . . . . . . . . . . . .
Final conclusions and prospects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author. Tel.: +36 62 599 768/769; fax: +36 62 433 188.
E-mail address: [email protected] (D. Dudits).
0168-9452/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.plantsci.2006.12.014
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P. Miskolczi et al. / Plant Science 172 (2007) 671–683
1. Introduction
The retinoblastoma susceptibility gene was the firstly
identified tumor suppressor and was isolated by positional
cloning from retinoblastoma tumors [1] that originated from the
thin membranous retina situated in the back of the eye. Since
then, many investigations showed a broad range of functions for
the retinoblastoma protein (pRB) in higher eukaryotic
organisms. The retinoblastoma gene family encodes a group
of related proteins that participate in several processes of cell
growth and differentiation, including cell cycle regulation and
control of gene expression [2–4]. It was shown more than a
decade ago, that many of the fundamental control mechanisms
that govern cell division in animals are also conserved in plants
[5–9]. The first retinoblastoma homologue gene of plant origin
was cloned from Zea mays [10–12]; subsequently similar genes
have been isolated from several other plant species, including
the dicot Nicotiana tabacum [13], Arabidopsis thaliana [14],
Medicago sativa and the monocot Oryza sativa [15].
Considering the phylogenetic conservation of several cell
cycle regulatory elements (CDKs; cyclins) between animals
and plants, one might predict that the retinoblastoma-related
plant homologues play a complex role, analogous to many
functions found in their animal counterparts. However, the
plant life cycle possesses several specific features compared to
animals, for example, plant development is largely postembryonic; cell divisions occur in specialized zones known as
meristems; somatic cells are totipotent. Therefore, we can
expect cell cycle regulatory elements in plants – including RB
proteins – to show a plant specific nature with respect to growth
and developmental control.
2. Conserved structure of the RB proteins
In order to evaluate the functional significance of RBs in
control mechanisms, it is worth discussing some of the
structural features of these proteins.
Since our present knowledge of the structural and functional
characteristics of the RB protein family is derived mainly from
the original RB protein itself, we use this 928 amino acid long
human RB protein to present the significant functional regions,
as summarized in Fig. 1.
The amino-terminal region of pRB (amino acids 1–378) is
crucial for embryonic and postnatal development, tumor
suppression and the functional integrity of the entire pRB
[16]. Results of in vitro experiments with purified recombinant
proteins and of yeast two-hybrid interaction tests have revealed
the self-association of the retinoblastoma protein and the
interaction of its amino- and carboxy-terminal regions [17].
The N-terminal domain also mediates interaction with a 84-kD
nuclear matrix protein [18], a cell cycle-regulated kinase [19],
and a heat-shock protein [20]. The p84N5 protein may regulate
pRB subcellular localization [18] and apoptosis suppression
[21]. This domain also binds to the MCM7 protein of the prereplication complex [22]; this data provides the first evidence
that pRB and RB-related proteins can directly regulate DNA
replication.
Fig. 1. Schematic representation of conserved features of the human pRB
protein and some plant counterparts. Numbers at the bottom of the bar delineate
amino acids comprising the amino terminus (N), A-pocket (A), spacer region,
B-pocket (B), C-domain (C). The underlined numbers show the amino acid
number of the border of the pockets. The same organizations of pocket domains
of plant RB-related proteins are also marked. The black balls represent the
approximate locations of potential CDK phosphorylation sites predicted by
NetPhosK 1.0 [140]. The accession numbers used in this figure are: HuRB
(AAA69807), AtRBR1 (AAF79146); MsRBR (AY941773); OsRBR1
(AY941774); OsRBR2 (AY941775).
The small pocket region that contains the A and B domains
(amino acids 379–572 and 646–772, respectively, separated by
a spacer), was originally identified as an essential part of the
pRB for the interaction with two viral oncoproteins: the SV40
large T-antigen and adenovirus E1A [23]. This region is
necessary for binding proteins containing a conserved LxCxE
amino acid motif, as the above mentioned viral proteins, the
human papillomavirus E7 [24], D-type cyclins [25], Elf-1 [26],
and a PP1 phosphatase containing a slightly modified version of
the LxCxE motif [27]. The importance of this region was
underlined by the fact that most of the RB mutations detected in
tumors affect at least either one of the A or B domains. A
specific characteristic of the structure of these domains is that
they contain a five-helix cyclin fold core [28]. Co-crystallization experiments demonstrate that the LxCxE peptide binds
a highly conserved groove on the B-domain portion of the
pocket; the A-domain portion appears to be required for the
stable folding of the B box [28].
The large pocket region of the pRB is composed of the small
pocket together with the C-terminal domain (amino acids 773–
928). The large pocket region of pRB is most noted for its
ability to bind a class of E2F transcription factors, but it is
crucial for interacting with most of the RB-associated proteins
identified so far (for review see [29]). Studies have indicated
that E2F and the LxCxE motif containing proteins bind on
separate sites on pRB [30].
The C-terminal domain alone has been defined by its
interaction with the c-Abl tyrosine kinase [31]. It has only a few
other known specific protein interactors, such as mdm2, the
p53-regulatory oncoprotein [32].
P. Miskolczi et al. / Plant Science 172 (2007) 671–683
In summary, discrete regions of pRB protein are involved in
different protein–protein interactions with diverse functional
consequences. The characteristics of these protein–protein
associations (like duration and strength) are largely dependent
on the most important post-translational modification of the
pRB: its phosphorylation on numerous S/T residues.
2.1. RB activity depends on the phosphorylation level
The mammalian pRB is phosphorylated at multiple sites in a
cell cycle-dependent manner; the bulk phosphorylation of pRB
sites can be accounted for by the activity of cyclin-dependent
kinases (CDKs). Hypophosphorylated, active forms of pRB
dominate in G1, whereas, hyperphosphorylated forms appear as
cells enter S phase and dominate in G2 and M phases [33].
Results of phosphopeptide analyses of pRB suggest more than a
dozen distinct sites of phosphorylation on either serine or
threonine residues [34]. Conversely, pocket protein dephosphorylation by protein phosphatase I is also known to occur in
the period from anaphase to G1 and prevents the cell from
entering into the next cell cycle [35]. It is also known that
protein phosphatase 2A can contribute to production of
hypophosphorylated pRB in S phase in response to girradiation induced DNA damage [36]. Oxidative stress can
also induce rapid PP2A-dependent dephosphorylation of pRB,
p107 and p130 [37].
2.2. Active pRB level depends also on proteolysis
While the pRB phosphorylation status depends on the
reversible action of kinases and phosphatases, in some
situations hyperphosphorylation may cause degradation of
pocket proteins [38], and consequently irreversibly decreases
the protein level. HPV 16 E7 protein induces degradation of
pRB proteins through the ubiquitin-proteosome pathway [39]
and degradation of pRB-related proteins p107 and p130 can
also happen by a proteosome-dependent mechanism [40].
Later, it was established that the ubiquitin-proteosome pathway
as well as calpain play a potential role in the degradation of the
p107 protein [41]. Interestingly, other human viruses can also
induce the degradation of the hypophosphorylated forms of the
retinoblastoma family member in a proteosome-dependent
manner [42]. Caspase-dependent cleavage of pRB was found to
participate in programmed cell death [43]; in the apoptotic
process, pRB became dephosphorylated and then immediately
cleaved into p48 and p68 fragments [44]. On the other hand,
caspase-9 can antagonize p53-induced apoptosis by generating
a p76 truncated pRB protein [45].
2.3. Specific tools for the analysis of general functions: RB
interacting partners
To date, at least 110 cellular proteins have been reported to
associate with the mammalian pRB. For extensive review, see
[29], which summarizes the literature of the possible
retinoblastoma associated partners in animals. According to
this article, the interaction partners fall largely into three groups
673
based on some similar characteristics. In the largest group,
there are about 70 reported transcriptional regulators which fall
into three basic functional categories when bound to pRB (a)
factors which repress transcription, (b) factors which activate
transcription, and (c) factors that affect transcription in
unknown or unclear ways. Secondly, there are more than a
dozen enzymes (kinases, phosphatases, and kinase-regulators);
most of these post-translationally modify pRB to affect its
function. Third and finally, there are more than 20 reported
interactors that have a variety of miscellaneous functions. A
large number of these proteins directly or indirectly regulate
DNA replication, the cell cycle and various nuclear processes.
Some of the pRB interactors are mentioned and discussed in
this review. A lot of binding partners of pRB with their various
functions in different processes play a key role of RB
homologue proteins in cellular events with an obvious
complexity, as discussed below.
3. Broad functions of the retinoblastoma protein family
in animals
In the middle of the past century the children’s retinoblastoma tumor was realized not only to occur sporadically, but
also to be inherited [46]. Cloning of the retinoblastoma
susceptibility gene [47] and identification of its mutations [48]
opened an innovative chapter in cancer molecular biology.
Soon, further retinoblastoma homologue genes were isolated,
and ever since they have been known as a family of pocket
proteins, consisting of three members, pRB, p107 [49] and
p130 [50] with partially overlapping roles in the life of the
mammalian cell [51].
3.1. Retinoblastoma family and cell cycle regulation
The pocket proteins are best known for their roles in
restraining the G1-S transition through the regulation of E2F
transcription factors (for review see [52]). Genes of the three
RB-family members vary in their expression patterns in
different tissues at various stages of the cell cycle. The pRB is
abundant during all phases of the cell cycle and exhibits only
slight variations in gene expression levels but with significant
differences in its phosphorylation status. p130 is detectable at
high levels in quiescent and differentiated cells, but its level
decreases rapidly when quiescent cells stimulated to re-enter
the cell cycle. In contrast, p107 levels are generally low in
terminally differentiated cells, but rise, when cells are
stimulated to proliferate and remain high throughout the
proliferative cell cycle [53]. Members of the pocket protein
family show a clear difference in their interaction capability
with various E2F transcription factors. pRB can bind activator
E2Fs (E2F1,2,3a) except for E2F3b, which functions mainly as
a repressor. In contrast, p107 and p130 preferentially bind
repressor-type E2Fs. Consequently, the pocket proteins not
only inhibit E2F mediated transactivation but also work
together with another set of E2Fs to repress transcription and
inhibit G1-S progression [2,52]. Targeted inactivation of all the
three RB-related genes in embryonic stem cell causes
674
P. Miskolczi et al. / Plant Science 172 (2007) 671–683
deregulated G1/S transition, abrogation of G1 arrest and the
lack of senescence in culture [54,55]. This confirms the
essential role of the pocket family in cell cycle control, G1/S
transition and in the tumorigenesis [3].
3.2. Relevance to cancer and developmental defects
Importantly, RB mutations have also been found in nonretinal cancers including sarcomas, small-cell lung, bladder,
breast and parathyroid cancers, which evidently show the
relevance of pRB role in the regulation of cell proliferation
[56]. p130 mutations are also involved in human cancers [57],
while the mutation of p107 up to now was shown to associate
only with B-cell lymphoma [58]. On the other hand,
homozygous rb knockout mice die before the 16th day, and
the mice homozygous for either p107 or p130 mutations appear
normal, while their double knockouts show mainly defective
limb development. These and other results support the
conclusion the major involvement of pRB is in tumor initiation
and tumor progression while p130 participates rather in tumor
progression [51]. It was also shown recently that the acute loss
of pRB in primary quiescent cells is sufficient for re-entry in the
cell cycle [59]. The RB-family members are differentially
expressed during mouse development and their ability to arrest
the cell cycle can be cell-type specific [60], which is also a
confirmation of distinct cellular and developmental functions
(for more details see the following reviews: [61,62]). Similarly
to mammal gene products, two members of the RB family in
Drosophila, RBF1 and RBF2 are co-expressed at several stages
of development; however, spatial and temporal differences are
evident, including partly complementary patterns of expression
in the embryonic central nervous system [63].
3.3. The role of pRB in the regulation of apoptosis
In the nullzygous rb knockout mice extensive unscheduled
apoptosis occurred in multiple cell lineage [64], which was
observed especially in tissues in which pRB was highly
expressed in normal animals [65]. This result underlines the
significant role of pRB in the process of apoptosis [66]. pRB
regulates apoptosis during development, and loss of its function
results deregulated growth and cell death, moreover, pRB has
been proposed to protect differentiating cells from apoptosis
[66]. In contrast, p53 guards against DNA-damage and
oncogene expression by inducing both cell cycle and apoptosis
[66]. E2F transcription factors, which are known to be targets of
pRB, play a significant role in this process, since apoptosis was
induced in transgenic mice ectopically expressing E2F1 [2].
4. Plant retinoblastoma-related proteins (RBR)
4.1. Retinoblastoma-related genes from plants
A partial cDNA clone of the first identified plant
retinoblastoma-related gene was isolated from Z. mays [10].
Subsequently, another cDNA was also isolated, which was
considered to be a partial coding sequence for ZmRBR
(ZmRBR2), the encoded protein was approximately 90%
identical to ZmRBR1[12]. The predicted protein products of
the open reading frames showed an analogous domain structure
to the animal RB family and showed a persuading similarity to
the A and B pocket region [10–12]. The amino acid identity
between plant and animal A/B pockets is approximately 30%.
Since the discovery of the first maize RB-related homologue, more and more genes encoding retinoblastoma-related
proteins have been isolated and characterized from plants.
One new RBR gene was discovered from maize itself [67],
two homologues were found in other monocot grasses, such as
rice (OsRBR1 and OsRBR2) and wheat (TaRBR1 and TaRBR2)
[15] and up to now one in Cocos nucifera (Acc.: AAM77469).
With no exception, only a single representative Rb
homologue sequence could be detected in dicot species so
far, including N. tabacum [13], A. thaliana [14], M. sativa [15],
Pisum sativum (Acc.: BAA88690) Euphorbia esula (Acc.:
AAF34803), Populus tremula Populus tremuloides (Acc.:
AAT61377). Furthermore, another homologue is also present
in the genome of the unicellular green flagellate, Chlamydomonas reinhardtii [68]. These observations highlight very
interesting differences between dicot and monocot species. One
might speculate that a more complex Rb pathway in monocot
grasses can be responsible for monocot specific responses to
plant hormones and developmental strategies.
Thus, RB homologue proteins appear to be key regulatory
elements of not only animals but also of plants. It is not
surprising, that significant similarity (higher than 70%) can be
realized in the A and B pockets of the deduced amino acid
sequences in all cases. In Fig. 1, we depicted the main
characteristics of four plant retinoblastoma related proteins
aligned to human pRB. It is obvious that the domain
organization in plant retinoblastoma proteins is as important
as in metazoans. Up to now, notable diversity can be seen only
in Drosophila in which only a very short spacer exists between
the pocket domains [69]. Additionally, the identification of the
RB-binding LxCxE peptide motif in plant D-type cyclins
[70,71] which can mediate the binding of RB in animal cells
and the presence of this motif in the plant viral replication
protein RepA [72] also support that the RB-mediated cell
division and differentiation pathways may also exist in plants.
The phylogenetic tree of known plant and a few typical animal
retinoblastoma family proteins (Fig. 2) clearly demonstrates that
the plant RBR proteins can be categorized into three distinct
subfamilies [15]. Subfamily A contains all dicots, while
Subfamily B and C represent all monocot RBR proteins.
Securely A. thaliana genome carries only a single retinoblastoma-related gene [14] and based on the available sequence
information and extensive in silico searches a single retinoblastoma homologue can be predicted for all dicots [15,73].
It is presumable that there could be important differences
between at least monocot grasses and dicots since a probable
gene duplication event allowed a functionally distinct
partitioning of the monocot RBR proteins [15,73]. Consequently, the two types of RBR proteins may suggest a more
complex RB pathway in grasses similar to the animal situation
[15,67,73].
P. Miskolczi et al. / Plant Science 172 (2007) 671–683
675
Fig. 2. Comparison of plant and animal Rb family members. Phylogenetic tree of RB homologues sequences from both plant and animal. The multiple alignment was
made by the ClustalW program and displayed by Phylodendron program (http://iubio.bio.indiana.edu/treeapp/). The scale beneath the tree measures the evolutionary
distance between sequences. The accession numbers of the sequences used in this study are: AtRBR1 (AAF79146); CrRBR (CAA09736); CnRBR (AAM77469);
CsRBR (BAE80326); EeRBR (AAF34803); GgRBR1 (AAA19644); GgRB2_p130 XM_414087; HsRB1(AAA69807); HsRBL1_p107 CAI95178; HsRBL2_p130
Q08999; MmRB1 AAH96525; MmRBL1_p107 AAH69179; MmRBL2_p130 2211351A; MsRBR (AY941773); NbRBR (AAU05979); NtRBR (BAA76477);
OsRBR1 (AY941774); OsRBR2 (AY941775); PsRBR (BAA88690); PtRBR (AAF61377); RnRB1 BAA04958; RnRBL2_p130 NP_112356; SbRBR (BAE06273);
TaRBR1 (AY941772); TaRBR2 (AY941776); ZmRBR1 (CAA67422); ZmRBR2 (CAC82493); ZmRBR2a (AAB69650); ZmRBR2b (AAB69651); ZmRBR3
(AAZ99092).
4.2. Expression profiles of the plant RBR subfamily genes
The point of interest of the numerous similarities to animals
is recruited also by the expression patterns of the two RBR
genes of O. sativa. In details, expression of the OsRBR1 gene
can be linked to cell division activity because it shows a higher
expression in young leaves and decreasing mRNA amounts
from the basal regions towards the tip in mature rice leaves [15].
Similarly, the division activity in developing maize leaves was
consistently the highest at the basal section and decreased with
the increasing distance from the leaf insertion point [74]. The
level of OsRBR2 transcripts was several hundred times higher
in fully mature leaves than the amounts of mRNA of OsRBR1
and OsRBR2 transcripts detected mostly in differentiated
tissues [15]. In maize at least one RBR gene is expressed in all
the tissues examined, with the highest levels seen in the shoot
apex, where the labelled probe could hybridize to both ZmRBR1
and ZmRBR2 [12]. RBR proteins can be detected both in
proliferating and differentiated tissues [11,12]. Increasing the
level of the 110 kDa form of ZmRBR1 is associated with the
exiting from cell division and entering to differentiation in leaf
cells [75], while expression of the RBR3 protein is restricted to
the mitotic stage during maize endosperm development [67].
This correlates well with the expression of OsRBR1 predominantly in mitoticaly active tissues [15].
In the case of dicot tobacco the mRNA level of NtRBR1
could be found in all organs examined [13], similarly to alfalfa,
where the MsRBR gene showed constitutive transcript levels in
all sections of mature leaves, in roots cells and suspension
culture [15]. Moreover, based on the expression data available
at the Genevestigator database, the AtRBR1 gene is expressed
constitutively in different organs [15].
Briefly, single dicot gene transcripts appear to be
ubiquitously expressed, while in the cereal monocot species
a clear specialization can be observed between the two RB
subfamilies already characterized and this suggests distinct
function of RBR subfamily members in monocot plants
[15,67].
4.3. Increasing number of known interactors of plant RBR
proteins
Based on their sequence, one can expect that plant RBR
proteins have similar biochemical properties compared to their
animal counterparts. Like human pRB, ZmRBR1 and ZmRBR3
are nuclear proteins that bind to both viral and cellular proteins
[12,75]. The ZmRBR1 protein can physically interact with
mammalian DNA tumor viral oncoproteins, the large-T antigen
of simian virus 40 [12] and adenovirus E1A [12], and HPV E7
[10,75]. This RBR species can also interact with plant viral
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replication-associated proteins, such as the RepA protein of
wheat dwarf virus [10,11,76] and the tomato golden mosaic
virus replication factor AL1 [12,14,77]. The reason so many
viral proteins associate with RBR is that many of these contain
an LxCxE consensus RB-binding motif, as it is necessary for
the Ad E1A, HPV E7 and the RepA proteins to be able to bind
to the in vitro translated ZmRBR3 protein in pull-down
experiments [67].
Furthermore, the intact LxCxE RBR-binding motif of the
replication-associated protein of Maize streak virus is required
for invasion of mesophyll cells but it is not necessary for the
infectivity of MSV in cereals [78]. The only one exception is the
AL1 protein that has a novel, suitably mapped domain instead
of the LxCxE motif [14,77]. Interestingly, the two identified
mutations in this domain affected AL1-RBR interactions in a
different manner and caused altered tissue specificity of
infection in plants [14].
Like most viruses, plant D-type cyclins also bind to ZmRBR1
[12,75] utilizing the conserved LxCxE motif for the interaction
with the ZmRBR1 protein [75]. Another verification of similar
interaction was demonstrated between NtRBR1 and Nicta;CycD3;1 using yeast two hybrid and in vitro binding assays [13].
Other types of cyclins, like the Medsa;CycA2 interacts also
with retinoblastoma when its cyclin box remains intact [79],
mammalian A-type cyclins also associates with retinoblastoma
family proteins as well, but in this case the N-terminal region
appears sufficient for binding [80].
It has been shown that ZmRBR1 binds E2F proteins from
mammals [12,75], wheat [81] and Arabidopsis [82] sources.
NtRBR1 can interact with NtE2F in a yeast two-hybrid assay
[83] that was confirmed also by in vitro pull-down assays [84].
This kind of interaction has also been shown recently between
the Arabidopsis E2FB and RBR1 proteins [85].
Finally, the list of published interactors of plant RBR
proteins can be finished at this moment with numerous
chromatin associated proteins, such as maize histone deacetylase (RPD3), which cooperates with ZmRBR1 in repressing
gene transcription [86] and WD-40 repeat protein LeMSI1 that
binds to the human pRB protein and the ZmRBR1 protein from
maize [87]. The CURLY LEAF (CLF) polycomb group protein
[88] and the recently characterized FVE (AtMSI4) protein also
showed association to the ZmRBR1 protein [89]. Besides,
another polycomb protein, the Arabidopsis fertilization
independent endosperm (FIE) interacts with human pRB and
its plant homologues from Arabidopsis (AtRBR1) and maize
(ZmRBR1), but surprisingly this interaction does not occur via
the assumed LxCxE conserved motif of the FIE protein [90].
These protein–protein interactions suggest that plant RBRs
play an important role in the regulation of gene expression
during plant cell cycle and development, involving chromatin
remodelling.
4.4. RBR activity is regulated post-transcriptionally by
phosphorylation
Dependence of the mammalian RB protein function on its
phosphorylation status is very well characterized and it is also
expected to play an important controlling tool of the plant RBR
protein regulation. Concerning this, the first finding was the
alteration of the ZmRBR1 phosphorylation state during
endosperm development. This protein was shown to be
phosphorylated in vitro by an E2F-associated cyclin dependent
kinase complex [10]. Just like human RB, ZmRBR1 was a good
in vitro substrate of three human G1/S cyclin/CDK complexes
[75]. The NtRBR1 protein of tobacco could be phosphorylated
in vitro by the tobacco cyclin D/Cdc2 complex [13] and this
kinase activity (cyclin D3;3/CDKA) was present only during
G1- to S-phases in synchronized tobacco BY-2 cells [91]. These
results are consistent with a previous report which showed that
a cell cycle regulated kinase activity was associated in vivo with
ZmRBR1 and this complex effectively phosphorylated the Cterminal domain of plant RBR protein in vitro [92]. Besides, it
has been recently shown that the maize RBR3 protein is also a
good substrate of the CycA1;3 associated kinase complex in
vitro [67]. In our experiments, the immunoprecipitated
MsCDKA;1/A;2 [93,94] complex could phosphorylate the
C-terminal region of MsRBR protein in vitro (P. Miskolczi,
manuscript in preparation), and the phosphorylation of the RBR
C-terminal fragment by MsCDKA;1 is sensitive towards the
inhibitory function of KRP from alfalfa [95].
4.5. Plant RBR proteins play a fundamental role in G1/S
transition
The revealed sequence and biochemical relations between
the plant and animal RB proteins with a high number of
homologue interactors strongly suggest that the functions of
plant retinoblastoma-related proteins share similarities to their
animal counterparts [73,96].
This prediction was supported by experimental results
demonstrating the reduced geminivirus DNA replication in
wheat cells transiently transfected with plasmids encoding
either ZmRBR1 or human p130 [11]. These data suggested that
ZmRBR1 controls the G1/S transition in plant cells and was
consistent with the fact that geminiviruses need an S-phase
environment for their replication [11], similarly to animal DNA
tumor viruses [97]. Secondly, in transient expression experiments, ZmRBR1 behaved as a transcriptional repressor (like
human pRB) and was capable of suppressing the transcriptional
activation by both human HBP1 (an LxCxE-containing
activator) and by E2F in human cells [75]. The next indication
of functional similarities was the ability of ZmRBR1 to repress
both AtE2Fa- and AtE2Fb-mediated transactivation in yeast
one-hybrid assays [82]. More recent results showed that the
transactivation by NtE2F/NtDP is repressed by co-transfection
of NtRBR1, and this repression effect could be overcome by
further co-expression of cyclin D in tobacco protoplasts [84].
These findings also underline the expectations that control of
cell cycle progression by RBRs through repression of
transactivation by E2Fs like to that in animals [2,52].
The above-mentioned results support the widely accepted
view that activation of G1/S transition in plants also depends on
an RBR control pathway [9,98–100]. It coincides with
hyperplastic growth induced by geminivirus infection [101]
P. Miskolczi et al. / Plant Science 172 (2007) 671–683
as well as the expression of the RepA protein stimulated cell
division in maize callus and tobacco BY2 cell culture where the
effect was reduced by over expression of the ZmRBR1 protein
[102].
In addition to the viral effects on host cells, the influence of
the ORF13 protein of the soil bacterium Agrobacterium
rhizogenes has been demonstrated on the plant cell cycle. This
protein contains the LxCxE RB-binding motif; therefore, its
interaction in vitro with human pRB can be explained [103].
The ectopic expression of ORF13 in tomato increased cell
division in the vegetative shoot apical meristem and accelerated
formation of leaf primordia. Mutations in the LxCxE motif
diminished the influence on cell division rates in the shoot
apical meristem, suggesting the possible role of RBR in
controlling cell cycle progression in meristematic tissue cells
primarily in G1-S phase transition [103].
Besides these facts, existence of six E2F transcription
factors and two DP genes in the Arabidopsis genome point to
the participation of plant RBR in complex transcription
regulation pathways [104]. Phenotypic characterizations of
plants overexpressing E2F family members revealed their
involvement in regulation of the cell cycle, differentiation, and
development [105–109], thus, the central role of the RB/E2F/
DP pathway in regulation of the above mentioned functions
have already been convincingly established [6,104].
4.6. Plant RBR functions in organogenesis
The detailed analysis of a series of RBR mutant plants can
provide new insight into the functional properties of RBR
proteins. The first reported mutant analysis was carried out on
homozygotic ZmRBR1 gene insertion mutants in maize, which
unexpectedly did not show any obvious phenotypic alterations
possibly due to redundancy provided by other RBR genes [96].
By this time, the first established answer to this question,
namely, the existence of a compensatory mechanism between
different RBR subfamily members in maize was strongly
proposed by results obtained in suspension culture where RepA
protein mediated inhibition of RBR1 activity was shown to
upregulate the RBR3 expression [67].
Analysis of A. thaliana insertion mutant plants, which have
only a single copy of the RBR genes, revealed gametophytic
lethality, and show certain developmental defects. Retinoblastoma homologue controlled nuclear proliferation in the female
gametophyte as a negative regulator during megagametophyte
development, as in rbr mutants failure of mitotic arrest of
haploid nuclei was observed [110]. Central nucleus initiated
autonomous endosperm development was reminiscent of
fertilization-independent seed ( fis) mutants [111], therefore,
AtRBR1 has an evident function in the cell cycle control during
gametogenesis and the repression of autonomous endosperm
development.
Two of the earlier mentioned interaction partners of RBR
proteins, FIE and MSI1 (WD proteins), are members of the
polycomb group (PcG), and their mutants show similar effects:
autonomous endosperm development in the absence of
fertilization [112–117]. FIE share homology with the mam-
677
malian protein embryonic ectoderm development (EED) [118]
and with Drosophila extra sex combs (ESC) PcG proteins [119]
which form complexes with other members of the PcG group
that repress transcription at specific genome sites by modifying
the chromatin structure at diverse developmental stages [120].
In animals MSI1 homologues, RbAp46 and RbAp48 interact
with the pRB protein [121] and these PcG members belong to
those histone deacetylase complexes which play an important
role in the modification of chromatin structure and function
[122]. The FVE protein that was shown to interact with
AtRBR1 and the fve mutant plants provide genetic evidence for
the regulation of flowering by repressing flowering locus C
(FLC) transcription through a histone deacetylation [89].
Additionally, an other chromatin modifier, the RPD3-type
histone deacetylase is involved in RBR-mediated transcriptional regulation, since its antisense expression in Arabidopsis
showed different pleotropic effects: changes in organ development including flower abnormality, male and female sterility,
asymmetric leaves and late flowering [86,123,124].
Moreover, the Arabidopsis chromatin assembly factor
(CAF-1), a heterotrimer of the MS11, FAS1 and FAS2 gene
products, is necessary for forming the correct temporal pattern
of expression of stem-cell marker genes, such as WUSCHEL
(WUS) and SCARECROW (SRC) in shoot or root apical
meristems, respectively [125]. As it was discussed above, the
MSI1 is an RBR interacting protein in plant [87], suggesting
that the participation of the RBR-dependent pathway in the
regulation of stem cell populations [104]. The role of RBR
pathway in stem cell maintenance has been approved
conclusively in Arabidopsis root, where the reduction of
RBR gene transcript level increased the amount of stem cell
layers without increasing the duration of the cell cycle, while
the induced over-expression of RBR protein abrogates the stem
cells [126]. This publication also presented some experimental
results on the downstream state of RBR-mediated regulation of
the SCR patterning gene [126]. Correspondingly, in shoot apical
meristem the local overexpression of the RBR protein is
sufficient to induce meristem cells into entering initial stages of
differentiation, also recently shown by using a microinduction
technique [127]. Results obtained by another type of RBR
inactivating experimental system, using the inducibly
expressed viral inhibitory RepA protein, revealed that RBR
limits a cell division in cell type specific manner during
Arabidopsis leaf development [128]. At the stage of leaf
development when cell proliferation was predominant, RBR
restricted cell division, while it controlled the frequency of the
endocycle at later phases [128]. Moreover, epidermal cells
retain the ability to re-enter the cell cycle, but maintain
epidermal cell fate, differently from the mesophyll cell layers
[128].
Phenotypic consequences from plants with modified RBR
protein levels or changed E2F binding activity indicate that the
plant retinoblastoma-related protein has an important cue not
only in cell cycle regulation but also in the developmental
context in plant organogenesis. This process likely involves a
way through chromatin regulation similar to animals
[129,130].
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P. Miskolczi et al. / Plant Science 172 (2007) 671–683
5. Final conclusions and prospects
The complexity of RBR functions in higher plants can be
concluded from the wide variety of roles of RBR proteins
discussed before [67,96,110,131]. It is assumptive that the
evolution of the RB pathway occurred after separation of
the fungi from the higher eukaryotic lineage, but preceded the
divergence of the plant and animal kingdoms [75]. While
animals have at least two homologues of pocket domain
proteins, it is an interesting finding that the monocot Gramineae
species similarly appear to have two distinct RBR subfamilies
[15,73], while only a single representative of this gene was
found in the full genome of the A. thaliana [14], and this feature
seeming to be common to all dicots [15,73]. These observations
strengthen the suggestion that divergent functions of RBRs can
contribute to monocot specific characteristics in terms of organ
development and re-activation of the cell division cycle.
Supporting this assumption, different expression profiles were
observed in endosperm and leaf development for distinct RBRs
in the case of the analyzed monocot species [15,67].
Interestingly, the characteristics of maize RBR3 are more
closely related to p107; for example, the expression of RBR3 is
restricted largely to the mitotic phase of endosperm development
in maize plant, similar to p107, which exhibits higher expression
levels in actively dividing mammalian cells in spite of the maize
RBR1 and mammalian pRB genes being constitutively expressing [53,67]. The well-known recalcitrance of cereals to genetic
transformation [132] could be a consequence of the possible
compensatory mechanism between RBR1 and RBR3, which is in
good correlation with facilitated growth and increased transformation efficiency of RepA protein expressing maize transformants [102]. Moreover, yeast two-hybrid analysis has revealed
that the Medicago PP2A B00 regulatory subunit, a strong
association partner of MsRBR, can interact with OsRBR1, but
there was no any detectable association with the OsRBR2 protein
[15]; similar characteristic was reported for mammalian pocket
proteins [133]. This finding also supported our suggestion that
plant RBRs belong to B and C subfamilies have different roles in
the regulation of plant cell division and differentiation. To advert
to these views remains an exciting point, what kind of functions
can be shared and how it consists of compensatory mechanisms
between subclasses of monocot RBR proteins. To give a valid
explanation to these questions, we should devote further
investigations to the monocot RBR family through detailed
analyses of different mutants and transgenics involved in the
RBR/E2F/CYCD regulating pathway.
As we discussed previously, zygotic lethality was observed
as a consequence of functional loss of the mouse Rb and
Drosophila Rbf genes [134,135] and in accordance with this,
Arabidopsis rbr1 mutants show female gametophyte lethality
and gametophytic maternal-effect embryo lethality [110]. The
effects in later postembryonic stage of organogenesis in
Arabidopsis can be investigated by changing active RBR
protein levels even in a cell specific manner by using different
approaches: e.g. root meristem-specific promoter was used to
drive an RBR RNAi silencing construct when the obvious
sensitivity of the Arabidopsis root stem cell population was
shown. Another good example is the induced RepA proteinbased pocket protein inactivation system, where distinct
responses were demonstrated in different cells in terms of
maintaining the balance between cell division and endoreplication during Arabidopsis leaf development [128]. These findings
affirm the link between RBR and gene expression patterns that
mediate stem cell maintenance and demonstrate that there
should be a balance between cell division and differentiation
needed for correct postembryonic development.
Results of studies using the virus-induced gene silencing
(VIGS) technique to investigate the cellular function of NbRBR1
in Nicotiana benthamiana strengthen the fact that plant
retinoblastoma homologues have a key role in negative
regulation of cell proliferation, differentiation and also in
endoreduplication [136]. The suppression of RBR causes
prolonged cell proliferation and causes extra DNA replication
in endoreduplicating leaf cells, that generates abnormal organ
development like partially retarded trichomes, abnormal leaf
formation and plant growth defects [136]. These phenotypes
correlated to transcriptional induction of E2F and E2F regulated
S-phase genes, indicating the release of E2F transcription factors
from RBR-mediated repression in G1/S transition [136].
Observations from other experiments connected to the E2F
homologues in plants also favour the generally accepted view
that RBR proteins possess a key role in controlling G1/S
transition [98–100,137], like in animals [52,138].
Analysis of further mutants of the RB connected pathways
could reveal new details in understanding the complex role of
controlling of such important mechanisms at both the cellular
and the whole organism level. As it turns out from the
continuously increasing examples of RBR interacting proteins,
plant retinoblastoma homologues are part of a multiprotein
complex (or dynamic multiprotein complexes) that supposedly
have an important mediating role in chromatin structure
regulation [88,90,115,137]. The RBR1/FIE/MSI1/MEA complex could be essential in repressing the activation of E2Fresponsive genes and controlling cell cycle, thus supervising
female gamete arrest, while fertilization starts the reinitiation of
the cell cycle in the Arabidopsis embryo sac [90,115]. These
recent results have given further support to the idea that plant
RBR members are also involved in chromatin regulation [88],
similarly to animals [129,130].
Nevertheless, identification of numerous interaction partners
of animal RB proteins and finding many of them in plants leave no
room for doubt that other RBR associated proteins will also be
identified in the near future even if the most characteristic classes
of the known partners have already been found in plants. We
should expect that it will help to clarify and approve some different functional aspects of the monocot RBR subfamilies [15].
While the in vitro phosphorylation of RBR proteins has been
demonstrated many times, the phosphatase activity on
hyperphosphorylated RBR has not been shown yet, although
it was thoroughly investigated in animals [139]. Other types of
regulation effects, like ubiquitin-dependent degradation of pRB
in animal cells [40] or caspase performed cleavage [44], is not
verified up to now and it remains a subject whether and how this
regulatory system operates in this respect in plants.
P. Miskolczi et al. / Plant Science 172 (2007) 671–683
679
Fig. 3. Summary of the RBR mediated pathway based on the results of the dicot Arabidopsis. The left panel shows the interaction partners of plant RBRs mentioned
in this review with their proposed relationships. A summary of the functional contributions based on the reported observations is shown in the middle of figure. The
right part of figure outlines the phenotypic effects on the known participants [141–148]. Abbreviations of types of experimental system: OE—over expression; LOF—
loss of function; VIGS—virus-induced gene silencing; AS—antisense, RNAi—RNA interference.
As we already know, the overall regulation of the cell cycle
is broadly parallel in plants and animals, but it is also admitted
that plants should deal with the environmental effects in the
same place because of their sessile nature and because
immobile cells with rigid cell walls have a proper developmental program which can correctly respond to internal and
external signals.
In order to summarize our current knowledge on the RBR
mediated pathways involved in cell cycle regulation and
organogenesis, we depicted a scheme of studied participants
along with their functional contribution and phenotypic
consequences in Fig. 3.
We hope that this comparative review can help to understand
the complex story about a protein originating from the purple
retina to its place in the green plant cell. Meanwhile, more and
more attention is being paid to its important role played also in
plants, about which many exciting questions are waiting to be
answered, to get more detailed understanding of cell cycle
regulation and organogenesis both in cereal crops and in dicot
plants as well.
Acknowledgments
We would like to thank Mátyás Cserháti for critical reading
of the manuscript. Gábor V. Horváth is grateful for the support
of the ‘‘János Bólyai’’ Research Fellowship.
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