Download Gene Section PAWR (PRKC apoptosis WT1 regulator protein) in Oncology and Haematology

Atlas of Genetics and Cytogenetics
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Gene Section
Mini Review
PAWR (PRKC apoptosis WT1 regulator protein)
Yanming Zhao, Vivek M Rangnekar
Department of Radiation Medicine, University of Kentucky, Combs Research Building, Room 309,
Lexington, Kentucky 40536, USA
Published in Atlas Database: August 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/PAWRID41641ch12q21.html
DOI: 10.4267/2042/38496
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Par-4/PAWR is ubiquitously expressed in normal
mammalian tissues. However, Par-4/PAWR is
diminished in a majority (>75% specimens) of renal
cell carcinoma specimens. Par-4/PAWR expression is
also decreased in endometrial tumors, neuroblastoma
and in cells of patients with acute lymphatic leukemia
and chronic lymphocytic leukemia.
Hugo: PAWR
Other names: Par-4 (Prostate apoptosis gene 4); PAR4
Location: 12q21.2
Local order: Synaptotagmin I 12q21.2 on plus strand
protein phosphatase 1, regulatory (inhibitor) subunit
12A 12q21.2 on minus strand PAWR 12q21.2 on
minus strand protein tyrosine phosphatase, receptor
type, Q 12q21.2 on plus strand.
Localisation
Immonocytochemical analysis indicates that Par4/PAWR is predominantly localized in cytoplasm in
normal cells and is strongly localized in cytoplasm and
nucleus in most cancer cell lines. However, Western
blot analysis indicates that Par-4/PAWR is also in the
nuclear fraction of normal cells implying it is masked
in the nucleus.
DNA/RNA
Description
Genomic regions: Par-4/PAWR gene is encoded by the
minus strand of chromosome 12q21.2. The gene
encompasses 99.064 kb of DNA; 7 exons and 6 introns.
ATG is located on exon 2.
Function
Transcription
Par-4/PAWR, a pro-apoptotic protein, was first
identified in prostate cancer cells that were induced to
undergo apoptosis. Par-4 knockout mice spontaneously
develop tumors of the liver, lung, and endometrium;
prostatic intraepithelial neoplasia, and an increased
frequency of estrogen-inducible tumors in the
endometrium and BBN-inducible tumors in the
bladder. Endogenous Par-4/PAWR expressed in normal
and cancer cells does not, by itself, causes apoptosis,
yet is essential for apoptosis via diverse cell death
pathways. Par-4/PAWR sensitizes cells to apoptosis by
wide variety of pro-apoptotic stimuli, such as growth
factor withdrawal, agents that elevate intracellular Ca2+,
TNF, TRAIL, UV, X-ray and gamma irradiation, or
IFN-gamma. Ectopic Par-4/PAWR over-expression is
by itself sufficient to induce apoptosis in most cancer
cells, but not in normal or immortalized cells. The
cancer selective pro-apoptotic function of Par-4/PAWR
is localized in its central core SAC (Selective for
Apoptosis-induction in Cancer cells) domain (amino
2.2 kb nucleotides mRNA. 1.02 kb open reading frame.
Pseudogene
Not known.
Protein
Description
Human Par-4/PAWR is a about 40 kDa protein
containing 340 amino acids. Rat Par-4 has 332 amino
acids whereas mouse Par-4 has 333 amino acids. Par4/PAWR has two putative nuclear localization
sequences in the N-terminal region and a leucine zipper
domain and a nuclear export sequence in the C-terminal
portion. There is a SAC domain (147-206 amino acids),
selective for apoptosis induction in cancer cells. SAC
domain is the effecter domain of Par-4/PAWR. These
domains are 100% conserved in human, rat and mouse
homologs.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2)
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PAWR (PRKC apoptosis WT1 regulator protein)
Zhao Y, Rangnekar V
acids 147-206 in human Par-4/PAWR; or 137-195 in
rat Par-4) which is 100% conserved in human, mouse
and rat. Apoptosis by ectopic Par-4/PAWR requires
Par-4/PAWR nuclear translocation and involves both
activation of the Fas death receptor signaling pathway
and NF-kappaB inhibition. Par-4/PAWR also inhibits
the prosurvival protein Bcl-2 and down regulates ERK2 expression. Neither p53 nor PTEN are directly
required for apoptosis by Par-4/PAWR or the SAC
domain. Par-4/PAWR has been shown to be involved
in suppression of transformation by down-regulation of
Ras. Overexpression of Par-4/PAWR results in
apoptosis of cells expressing oncogenic Ras.
Several partner proteins of Par-4/PAWR have been
identified and partner interaction requires an intact Par4/PAWR leucine zipper domain. Par-4/PAWR
associates with aPKC resulting in inhibition of NFkappaB activity, interaction with WT1 results in
transcriptional repression of Bcl-2, whereas binding to
and phosphorylation by Akt1 results in Par-4/PAWR
cytoplasm retention by 14-3-3, thus isolating Par4/PAWR from its nuclear targets. Par-4/PAWR also
binds to DLK/ZIP kinase (ZIPK) and induces
DAAX/ZIPK-mediated apoptosis. In addition, THAP1
(a novel nuclear pro-apoptotic factor) interacts with
Par-4/PAWR and potentiates both serum withdrawal
and TNF-induced apoptosis in endothelial cells.
Par-4/PAWR is also involved in sensitization of
neurons to apoptosis. Endogenous Par-4/PAWR is
reported
to
be
up-regulated
in
different
neurodegenerative diseases including Alzheimer's,
Huntington's and Parkinson's diseases and amyotrophic
lateral sclerosis.
Post-translational modifications: The apoptosis of Par4/PAWR requires phosphorylation of the threonine
residue (T155 in rat Par-4/PAWR) in the SAC domain
by PKA, which is elevated in cancer cells. Amino acid
S249 in rat Par-4/PAWR is phosphorylated by AKT for
Par-4/PAWR cytoplasm retention and inactivation.
Implicated in
Renal cell carcinoma and endometrial
tumors
Note: Par-4/PAWR is down regulated in over 75% of
clear cell type of renal cell carcinoma, and in
endometrial tumors. It is mutated within its effector
SAC domain in endometrial tumors.
References
Sells SF, Wood DP Jr, Joshi-Barve SS, Muthukumar S, Jacob
RJ, Crist SA, Humphreys S, Rangnekar VM. Commonality of
the gene programs induced by effectors of apoptosis in
androgen-dependent and -independent prostate cells.. Cell
Growth Differ 1994;5:457-466.
Díaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J,
Sanz L, Moscat J. The product of Par-4, a gene induced during
apoptosis, interacts selectively with the atypical isoforms of
protein kinase C. Cell 1996;86:777-786.
Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S,
Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T,
Rangnekar VM, Shi Y. A novel repressor, Par-4, modulates
transcription and growth suppression functions of the Wilms'
tumor suppressor WT1. Mol Cell Biol 1996;16(12):6945-6956.
Sells SF, Han SS, Muthukkumar S, Maddiwar N, Johnstone R,
Boghaert E, Gillis D, Liu G, Nair P, Monnig S, Collini P,
Mattson MP, Sukhatme VP, Zimmer SG, Wood DP Jr,
McRoberts JW, Shi Y, Rangnekar VM. Expression and function
of the leucine zipper protein Par-4 in apoptosis. Mol Cell Biol
1997;17:3823-3832.
Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V,
Rangnekar VM, Mattson MP. Par-4 is a mediator of neuronal
degeneration associated with the pathogenesis of Alzheimer
disease. Nat Med 1998;4:957-996.
Johnstone RW, Tommerup N, Hansen C, Vissing H, Shi Y.
Mapping of the human PAWR (Par-4) gene to chromosome
12q21. Genomics 1998;53(2):241-243.
Díaz-Meco MT, Lallena MJ, Monjas A, Frutos S, Moscat J.
Inactivation of the inhibitory kappaB protein kinase/nuclear
factor kappaB pathway by Par-4 expression potentiates tumor
necrosis factor alpha-induced apoptosis. Bio l Chem
1999;274(28):19606-19612.
Homology
Duan W, Rangnekar VM, Mattson MP. Prostate apoptosis
response-4 production in synaptic compartments following
apoptotic and excitotoxic insults: Evidence for a pivotal role in
mitochondrial dysfunction and neuronal degeneration. J
Neurochem 1999;72:2312-232.
The Par-4/PAWR gene has been identified in various
organisms, including mammals (Pan troglodytes),
rodents (mouse, rat), chicken (Gallus gallus), fish
(Zebrafish and Pufferfish) and tadpole. The nuclear
localization, leucine zipper, nuclear export and SAC
domain sequences are highly conserved.
Nalca A, Qiu SG, El-Guendy N, Krishnan S, Rangnekar VM.
Oncogenic Ras sensitizes cells to apoptosis by Par-4. J Biol
Chem 1999;274(42):29976-29983.
Mutations
Duan W, Guo Z, Mattson MP. Participation of Par-4 in the
degeneration of striatal neurons induced by metabolic
compromise with 3-nitropropionic acid. Exp Neurol 2000;165:111.
Note: Par-4/PAWR mutations are uncommon although
a single base mutation (Arg (CGA) 189 (TGA) Stop)
localized in exon 3 or the SAC domain has been found
in endometrial carcinoma.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2)
Pedersen WA, Luo H, Kruman I, Kasarskis E, Mattson MP.
The prostate apoptosis response-4 protein participates in
123
PAWR (PRKC apoptosis WT1 regulator protein)
Zhao Y, Rangnekar V
motor neuron degeneration in amyotrophic lateral sclerosis.
FASEB J 2000;14:913-924.
Lafuente MJ, Martin P, Garcia-Cao I, Diaz-Meco MT, Serrano
M, Moscat J. Regulation of mature T lymphocyte proliferation
and differentiation by Par-4. EMBO J 2003;22(18):4689-4698.
Chakraborty M, Qiu SG, Vasudevan KM, Rangnekar VM. Par-4
drives trafficking and activation of Fas and FasL to induce
prostate cancer cell apoptosis and tumor Regression. Cancer
Research 2001;61:7255-7263.
Goswami A, Burikhanov R, de Thonel A, Fujita N, Goswami M,
Zhao Y, Eriksson JE, Tsuruo T, Rangnekar VM. Binding and
phosphorylation of Par-4 by Akt is essential for cancer cell
survival. Mol. Cell 2005;20(1):33-44.
Gurumurthy S, Vasudevan KM, Rangnekar VM. Regulation of
apoptosis in prostate cancer. Cancer Metastasis Rev
2001;20(3-4):225-243.
Gurumurthy S, Goswami A, Vasudevan KM, Rangnekar VM.
Phosphorylation of Par-4 by protein kinase A is critical for
apoptosis. Mol Cell Biol 2005;25:1146-1161.
El-Guendy N, Rangnekar VM. Apoptosis by Par-4 in cancer
and neurodegenerative diseases. Exp Cell Res 2003;283:5166. (Review).
Moreno-Bueno G, Fernandez-Marcos PJ, Collado M, Tendero
MJ, Rodriguez-Pinilla SM, Garcia-Cao I, Hardisson D, DiazMeco MT, Moscat J, Serrano M, Palacios J. Inactivation of the
candidate tumor suppressor Par-4 in endometrial cancer.
Cancer Res 2007;67(5):1927-1934.
El-Guendy N, Zhao Y, Gurumurthy S, Burikhanov R,
Rangnekar VM. Identification of a unique core domain of Par-4
sufficient for selective apoptosis-induction in cancer cells. Mol
Cell Biol 2003;23:5516-5525.
This article should be referenced as such:
Kawai T, Akira S, Reed JC. ZIP kinase triggers apoptosis from
nuclear PML oncogenic
domains. Mol Cell Biol
2003;23(17):6174-6186.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2)
Zhao Y, Rangnekar V. PAWR (PRKC apoptosis WT1 regulator
protein).
Atlas
Genet
Cytogenet
Oncol
Haematol.
2008;12(2):122-124.
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