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Gene Section
Review
BCLAF1 (BCL2-associated transcription factor 1)
John Peter McPherson
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5S 1A8 Canada
(JPM)
Published in Atlas Database: June 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/BCLAF1ID43164ch6q23.html
DOI: 10.4267/2042/46079
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
Two transcripts 5 kb and 3 kb in length are
predominantly detected, however additional variant
transcripts have been described with alternative
promoters, cassette exons and polyadenylation sites.
Other names: BTF; KIAA0164; bK211L9.1
HGNC (Hugo): BCLAF1
Location: 6q23.3
Local order: Orientation on minus strand, flanked by
FAM54A and MAP7 (according to GeneLoc and NCBI
Map Viewer).
Note: BCLAF1 was originally identified as a protein
partner for adenoviral E1B 19K. Forced expression of
BCLAF1 causes cell death which is reversed in the
presence of anti-apoptotic BCL-2. BCLAF1 was
reported to associate in vitro with BCL-2 and BCL2L1.
BCLAF1 was also reported to bind DNA and repress
transcription. Taken together, these findings suggested
a role for BCLAF1 in apoptotic signalling and
transcriptional repression (Kasof et al., 1999).
Subsequent studies using BCLAF1-depleted or Bclaf1deficient cells do not reveal a critical role for BCLAF1
in death signalling (Ziegelbauer et al., 2009;
McPherson et al., 2009). Recent studies have suggested
roles for BCLAF1 in processes of RNA metabolism
(Bracken et al., 2008; Sarras et al., 2010), KSHV viral
production (Ziegelbauer et al., 2009), lung
development and T cell activation (McPherson et al.,
2009; Kong et al., 2011).
Pseudogene
None identified.
Protein
Description
At least 4 isoforms are generated by alternative
splicing. Two predominant BCLAF1 forms were
initially described: a longer isoform 920 amino acids in
length with a predicted molecular mass of 106 kDa, and
a smaller isoform missing 49 amino acids (residues
797-846) with a predicted molecular mass of 101 kDa
(Kasof et al., 1999). Residues 110-126 exhibit 88%
homology to the bZIP DNA binding domain (Kasof et
al., 1999). Residues 522-531 exhibit 80% homology to
the Myb DNA binding domain (Kasof et al., 1999).
Functional evidence for both of these domains remains
to be shown. The N-terminal region (residues 3-161) of
BCLAF1 is arginine- and serine-rich (RS domain). The
C-terminal region (residues 512-913) is 59% similar to
the C-terminal region of thyroid hormone receptor
associated protein 3 (THRAP3/TRAP150).
DNA/RNA
Expression
Description
BCLAF1 is ubiquitously expressed, with high steadystate mRNA levels in skeletal muscle,
The BCLAF1 gene is composed of 13 exons and spans
32989 bases.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
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BCLAF1 (BCL2-associated transcription factor 1)
McPherson JP
Protein domains in BCLAF1L and BCLAF1S isoforms.
haematopoietic cells, and various other cell lineages
(Kasof et al., 1999; McPherson et al., 2009). Steadystate levels of BCLAF1 protein fluctuate in a temporal
and cell-lineage dependent fashion during development
(McPherson et al., 2009).
Bclaf1-deficient cells were found to exhibit altered
preferences for alternative splicing of a model substrate
(Sarras et al., 2010). BCLAF1 was found associated
with SkIP, TRAP150 and Pinin in a complex known as
SNIP1. SNIP1 was found to regulate cyclin D1 mRNA
processing by facilitating the recruitment of the RNA
processing factor U2AF65 to cyclin D1 mRNA
(Bracken et al., 2008).
BCLAF1 has been shown to complex with the RNA
export factor TAP/NXF1 (Sarras et al., 2010). This
property has also recently been reported for TRAP150,
a protein showing structural similarity to BCLAF1 that
also is found in ribonucleoprotein complexes (Lee et
al., 2010). TRAP150 has been shown to promote premRNA splicing of reporter substrates and promotes
mRNA decay in a manner that is independent of
nonsense-mediated decay of mRNA (Lee et al., 2010).
Regulation
Sirt1 has been shown to exert transcriptional control of
BCLAF1 at the promoter level (Kong et al., 2011).
Sirt1 was found to form a complex with the histone
acetyltransferase p300 and NF-kB transcription factor
Rel-A, bind the BCLAF1 promoter and suppress
BCLAF1 transcription via H3K56 deacetylation (Kong
et al., 2011).
BCLAF1 protein levels fluctuate according to cell
cycle position, with levels highest during the G1 phase,
but lower during S and G2 phases (Bracken et al.,
2008). BCLAF1 protein levels also fluctuate in a celllineage and temporal manner during differentiation of
certain tissues and organs (McPherson et al., 2009).
Several studies have determined that Bclaf1 is
extensively phosphorylated, although the functional
significance of this modification is unclear. BCLAF1
has been proposed as a substrate of GSK-3 kinase
(Linding et al., 2007). Vasopressin action in kidney
cells has been reported to simulate BCLAF1
phosphorylation (Hoffert et al., 2006).
BCLAF1 has been shown to be one of the cellular
targets for microRNAs (miRNAs) encoded by Kaposi's
sarcoma-associated herpesvirus (KSHV). KSHV
triggers certain acquired immune deficiency syndromerelated malignancies such as Kaposi's sarcoma, primary
effusion lymphoma and variants of multicentric
Castleman disease. A miRNA cluster within the KSHV
genome is expressed during viral latency. During
induction of lytic KSHV growth, inhibition of miRNAs
was associated with increased BCLAF1 expression and
Localisation
Bclaf1 is concentrated in punctate foci interspersed
through the nucleus. In the presence of E19K and
conditions which trigger apoptosis, the nuclear
distribution of Bclaf1 appears to concentrate at the
nuclear periphery or envelope (Kasof et al., 1999;
Haraguchi et al., 2004).
Bclaf1 was identified as a protein component of
interchromatin granular clusters, subnuclear structures
that appear to serve as repositories for pre-mRNA
splicing factors (Misteli and Spector, 1998; Sutherland
et al., 2001; Saitoh et al., 2004).
Function
The exact molecular function of BCLAF1 remains to
be defined. BCLAF1 was originally identified as
having properties of a death-inducing transcriptional
repressor (Kasof et al., 1999). Several subsequent
studies have expanded on the link between BCLAF1,
transcription and apoptosis. Depletion of BCLAF1 was
reported to render cells resistant to ceramide-induced
apoptosis (Renert et al., 2009). Protein kinase C deltamediated transactivation of p53 transcription has been
shown to occur through the stimulation of BCLAF1 to
co-occupy a core promoter element in the TP53
promoter (Liu et al., 2007). A role for Bclaf1 in lung
development and T cell homeostasis was demonstrated
in Bclaf1-deficient mice (McPherson et al., 2009).
Bclaf1 was shown to be required for the proper spatial
and temporal organization of smooth muscle lineage
cells during the saccular stage of lung development.
Bclaf1 was also shown to be critical for T cell
activation. The phenotype of these mice could not be
explained by a defect in apoptosis, furthermore Bclaf1deficient cells displayed no defect in cell death
following exposure to various apoptotic stimuli.
Recent studies have implicated BCLAF1 in processes
linked to RNA metabolism. BCLAF1 contains an RS
domain, a feature of many factors that facilitate premRNA splicing and mRNA processing. BCLAF1 was
found to be a component of ribonucleoprotein
complexes (Merz et al., 2007; Sarras et al., 2010).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
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BCLAF1 (BCL2-associated transcription factor 1)
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decreased KSHV virion production (Ziegelbauer et al.,
2009).
Interactions
E1B 19K. By yeast two-hybrid analysis, BCLAF1 was
shown to directly interact with adenoviral E1B 19K via
a BH3 domain and another region immediately
adjacent to BH3 in E1B 19K (Kasof et al., 1999). In
vitro binding assays reported BCLAF1 associates with
BCL-2 and BCL2L1.
emerin. By yeast-two hybrid analysis and microtiter
well binding assays, BCLAF1 was shown to directly
interact with emerin, a nuclear membrane protein.
Mutations that result in a loss of functional emerin
cause X-linked recessive Emery-Dreifuss muscular
dystrophy. The residues of emerin required for binding
to BCLAF1 mapped to two regions that flank its laminbinding domain. Two disease-causing mutations in
emerin, S54F and Delta95-99, disrupted binding to
BCLAF1. BCLAF1 and emerin were observed to colocalize in the vicinity of the nuclear envelope
following induction of apoptosis by Fas antibody
(Haraguchi et al., 2004).
MAN1. The C-terminal domain of MAN1, a nuclear
inner membrane protein that inhibits Smad signaling
downstream of transforming growth factor beta, was
observed to bind BCLAF1, as well as the
transcriptional regulators GCL, and barrier-toautointegration factor (BAF) (Mansharamani and
Wilson, 2005).
Factors that participate in RNA metabolism.
BCLAF1 and TRAP150 have been identified to be
protein components of ribonucleoprotein complexes
that participate in pre-mRNA splicing and other mRNA
processing events (Merz et al., 2007; Sarras et al.,
2010; Lee et al., 2010). Both BCLAF1 and TRAP150
have been reported to reside in protein complexes that
contain the mRNA export factor NXF1/TAP (Sarras et
al., 2010; Lee et al., 2010). Both BCLAF1 and
TRAP150, together with Pinin and SkIP, have been
found in a protein complex that regulates cyclin D1
mRNA stability.
Implicated in
X-linked recessive Emery-Dreifuss
muscular dystrophy
Note
Bclaf1 has also recently been identified as a binding
partner for emerin, a nuclear membrane protein that is
mutated in X-linked recessive Emery-Dreifuss
muscular dystrophy. Disease mutations in emerin were
found to disrupt the interaction of emerin with
BCLAF1 (Haraguchi et al., 2004).
Disease
Emerin is encoded by the EMD gene located on human
X-chromosome, which when mutated, gives rise to the
X-linked form of Emery-Dreifuss muscular dystrophy
(Bione et al., 1994). Emerin is a lamin A/C binding
protein that participates in nuclear envelope mechanics
which impact chromosome segregation, gene
expression and muscle differentiation (Liu et al., 2003;
Frock et al., 2006).
Choroid plexus papillomas
Note
Up-regulation of BCLAF1 was observed in seven cases
of choroid plexus papilloma cells compared to eight
cases of normal choroid plexus epithelial cells
(Hasselblatt et al., 2009).
Disease
Choroid plexus papillomas are rare intraventricular
papillary neoplasms, typically in children and young
adults.
Non-Hodgkin's lymphoma (NHL)
Note
An association of BCLAF1 single nucleotide
polymorphisms (tagSNPs rs797558 and rs703193, P =
0.0097) with NHL was made following genotyping of
441 newly diagnosed NHL cases and 475 frequencymatched controls (Kelly et al., 2010).
Disease
Non-Hodgkin's lymphoma refers to several subtypes of
lymphoma that are distinct from Hodgkin's lymphoma,
such as Mantle cell lymphoma, diffuse large B cell
lymphoma and follicular lymphoma (Sawas et al.,
2011).
Homology
BCLAF1 shares amino acid similarity (48% overall
identity) with TRAP150 in their C-terminal domains.
Both proteins also contain RS-rich tracts within their
N-termini (Lee et al., 2010).
Chondromyxoid fibroma (CMF)
Mutations
Note
No changes in BCLAF1 were found in 43 samples of
CMF (Romeo et al., 2010).
Disease
Chondromyxoid fibroma (CMF) is an uncommon
benign cartilaginous tumor of bone usually occurring in
adolescents (Ralph, 1962; Romeo et al., 2009). CMF is
associated
with recurrent rearrangements of
chromosome bands 6p23-25, 6q12-15, and 6q23-27.
Note
BCLAF1 is located at chromosome 6q23 , a region that
has been reported to exhibit a high frequency of
deletions in tumours, such as lymphomas and
leukemias. BCLAF1 has observed to be absent in Raji
cells, derived from Burkitt's lymphoma, which has
deletions in 6q (Kasof et al., 1999). A role for the loss
of BCLAF1 in neoplastic transformation remains to be
determined and may be coincidental.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
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BCLAF1 (BCL2-associated transcription factor 1)
McPherson JP
Bracken CP, Wall SJ, Barré B, Panov KI, Ajuh PM, Perkins
ND. Regulation of cyclin D1 RNA stability by SNIP1. Cancer
Res. 2008 Sep 15;68(18):7621-8
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This article should be referenced as such:
McPherson JP. BCLAF1 (BCL2-associated transcription factor
1). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(12):994997.
Merz C, Urlaub H, Will CL, Lührmann R. Protein composition of
human mRNPs spliced in vitro and differential requirements for
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