Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine protein phosphatases. A large body of evidence suggests that PP2A is a tumor suppressor and plays critical roles in regulating apoptosis. PP2A is a heterotrimeric protein complex. Its substrate specificity, localization, and activity are regulated by regulatory subunits of PP2A. A recent study has demonstrated that single nucleotide polymorphism in B56ε (PPP2R5E), a B56 family regulatory subunit of PP2A, is associated with human soft tissue sarcoma. This raises the possibility that B56ε is involved in tumorigenesis and plays important roles in regulating apoptosis. However, this hypothesis has not been tested experimentally. Our previous studies revealed that B56ε regulates a number of developmental signaling pathways during early embryonic patterning. Here we report novel functions of B56ε in regulating apoptosis. We provide evidence that B56ε has both anti- and pro-apoptotic functions. B56ε suppresses p53-independent apoptosis during neural development, but triggers p53-dependent apoptosis. Mechanistically, B56ε regulates the p53-dependent apoptotic pathway solely through controlling the stability of p53 protein. In addition to its function in regulating apoptosis, we show that B56ε undergoes proteolytic cleavage. The cleavage of B56ε is mediated by caspase-3 and occurs on the carboxyl side of an evolutionarily conserved N-terminal "DKXD" motif. These results demonstrate that B56ε, a substrate of caspase-3, is an essential regulator of apoptosis. So far, we have identified an alternative translation isoform and a caspase cleavage product of B56ε. The significance of post-transcriptional regulation of B56ε is discussed.
Alam,
Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells.
1999, Pubmed
Alam,
Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells.
1999,
Pubmed
Algeciras-Schimnich,
Apoptosis-independent functions of killer caspases.
2002,
Pubmed
Arroyo,
Involvement of PP2A in viral and cellular transformation.
2005,
Pubmed
Bennin,
Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B' subunits in active complexes and induces nuclear aberrations and a G1/S phase cell cycle arrest.
2002,
Pubmed
Bertoli,
Calpain small-1 modulates Akt/FoxO3A signaling and apoptosis through PP2A.
2009,
Pubmed
Chen,
Cancer-associated PP2A Aalpha subunits induce functional haploinsufficiency and tumorigenicity.
2005,
Pubmed
Chen,
Heterogeneity of transcriptional activity of mutant p53 proteins and p53 DNA target sequences.
1993,
Pubmed
Cho,
Structural basis of PP2A inhibition by small t antigen.
2007,
Pubmed
Cho,
Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme.
2007,
Pubmed
Cohen,
Novel protein serine/threonine phosphatases: variety is the spice of life.
1997,
Pubmed
Colella,
Reduced expression of the Aalpha subunit of protein phosphatase 2A in human gliomas in the absence of mutations in the Aalpha and Abeta subunit genes.
2001,
Pubmed
Cordenonsi,
Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads.
2003,
Pubmed
,
Xenbase
De Botton,
Platelet formation is the consequence of caspase activation within megakaryocytes.
2002,
Pubmed
Demetrick,
Chromosomal mapping of the genes for the human cell cycle proteins cyclin C (CCNC), cyclin E (CCNE), p21 (CDKN1) and KAP (CDKN3).
1995,
Pubmed
Eichhorn,
Protein phosphatase 2A regulatory subunits and cancer.
2009,
Pubmed
Fernando,
Caspase 3 activity is required for skeletal muscle differentiation.
2002,
Pubmed
Gauci,
Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.
2009,
Pubmed
Giaime,
Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6.
2010,
Pubmed
Giaime,
Caspase-3-derived C-terminal product of synphilin-1 displays antiapoptotic function via modulation of the p53-dependent cell death pathway.
2006,
Pubmed
Gjoerup,
Induction of p53-independent apoptosis by simian virus 40 small t antigen.
2001,
Pubmed
Green,
Cytoplasmic functions of the tumour suppressor p53.
2009,
Pubmed
Grochola,
Recent natural selection identifies a genetic variant in a regulatory subunit of protein phosphatase 2A that associates with altered cancer risk and survival.
2009,
Pubmed
Hensey,
A developmental timer that regulates apoptosis at the onset of gastrulation.
1997,
Pubmed
,
Xenbase
Hensey,
Programmed cell death during Xenopus development: a spatio-temporal analysis.
1998,
Pubmed
,
Xenbase
Howe,
Identification of a developmental timer regulating the stability of embryonic cyclin A and a new somatic A-type cyclin at gastrulation.
1995,
Pubmed
,
Xenbase
Janssens,
Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling.
2001,
Pubmed
Jiang,
Cytochrome C-mediated apoptosis.
2004,
Pubmed
Jin,
The 48-kDa alternative translation isoform of PP2A:B56epsilon is required for Wnt signaling during midbrain-hindbrain boundary formation.
2009,
Pubmed
,
Xenbase
Kateneva,
Shugoshin and PP2A: collaborating to keep chromosomes connected.
2009,
Pubmed
Kawashima,
Phosphorylation of H2A by Bub1 prevents chromosomal instability through localizing shugoshin.
2010,
Pubmed
Kimura,
Cyclin G1 associates with MDM2 and regulates accumulation and degradation of p53 protein.
2002,
Pubmed
Krueger,
Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex.
2001,
Pubmed
Li,
The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A.
1996,
Pubmed
Li,
B56-associated protein phosphatase 2A is required for survival and protects from apoptosis in Drosophila melanogaster.
2002,
Pubmed
Li,
A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55.
2007,
Pubmed
Lin,
PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum.
2006,
Pubmed
Liu,
A functional genomics analysis of the B56 isoforms of Drosophila protein phosphatase 2A.
2007,
Pubmed
Manning,
The protein kinase complement of the human genome.
2002,
Pubmed
McCright,
Identification of a new family of protein phosphatase 2A regulatory subunits.
1995,
Pubmed
Miossec,
Evidence for CPP32 activation in the absence of apoptosis during T lymphocyte stimulation.
1997,
Pubmed
Moody,
Fates of the blastomeres of the 16-cell stage Xenopus embryo.
1987,
Pubmed
,
Xenbase
Mumby,
PP2A: unveiling a reluctant tumor suppressor.
2007,
Pubmed
Nojima,
Protein kinases that regulate chromosome stability and their downstream targets.
2006,
Pubmed
Okamoto,
Cyclin G recruits PP2A to dephosphorylate Mdm2.
2002,
Pubmed
Okamoto,
p53-dependent association between cyclin G and the B' subunit of protein phosphatase 2A.
1996,
Pubmed
Peng,
DNA damage signaling in early Xenopus embryos.
2008,
Pubmed
,
Xenbase
Posmantur,
Caspase-3-like activity is necessary for IL-2 release in activated Jurkat T-cells.
1998,
Pubmed
Rivera,
Shugoshin and PP2A, shared duties at the centromere.
2006,
Pubmed
Rodrigues,
p53 mutations in colorectal cancer.
1990,
Pubmed
Rorick,
PP2A:B56epsilon is required for eye induction and eye field separation.
2007,
Pubmed
,
Xenbase
Ruediger,
Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the A alpha subunit gene.
2001,
Pubmed
Ruediger,
Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the A beta subunit gene.
2001,
Pubmed
Ruvolo,
PKR regulates B56(alpha)-mediated BCL2 phosphatase activity in acute lymphoblastic leukemia-derived REH cells.
2008,
Pubmed
Sablina,
SV40 small T antigen and PP2A phosphatase in cell transformation.
2008,
Pubmed
Sablina,
The role of PP2A A subunits in tumor suppression.
2007,
Pubmed
Sablina,
The tumor suppressor PP2A Abeta regulates the RalA GTPase.
2007,
Pubmed
Saraf,
Differential expression of the B'beta regulatory subunit of protein phosphatase 2A modulates tyrosine hydroxylase phosphorylation and catecholamine synthesis.
2007,
Pubmed
Schwerk,
Non-apoptotic functions of caspases in cellular proliferation and differentiation.
2003,
Pubmed
Shen,
p53-dependent apoptosis pathways.
2001,
Pubmed
Shi,
Serine/threonine phosphatases: mechanism through structure.
2009,
Pubmed
Shouse,
Serine 15 phosphorylation of p53 directs its interaction with B56gamma and the tumor suppressor activity of B56gamma-specific protein phosphatase 2A.
2008,
Pubmed
Sible,
Zygotic transcription is required to block a maternal program of apoptosis in Xenopus embryos.
1997,
Pubmed
,
Xenbase
Silverstein,
Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits.
2002,
Pubmed
Stack,
Developmentally regulated activation of apoptosis early in Xenopus gastrulation results in cyclin A degradation during interphase of the cell cycle.
1997,
Pubmed
,
Xenbase
Suganuma,
Okadaic acid: an additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter.
1988,
Pubmed
Trinkle-Mulcahy,
Mitotic phosphatases: no longer silent partners.
2006,
Pubmed
Tsao,
Mitochondrial protein phosphatase 2A regulates cell death induced by simulated ischemia in kidney NRK-52E cells.
2007,
Pubmed
Vaseva,
The mitochondrial p53 pathway.
2009,
Pubmed
Veenstra,
Non-cell autonomous induction of apoptosis and loss of posterior structures by activation domain-specific interactions of Oct-1 in the Xenopus embryo.
1998,
Pubmed
,
Xenbase
Virshup,
From promiscuity to precision: protein phosphatases get a makeover.
2009,
Pubmed
Vousden,
Live or let die: the cell's response to p53.
2002,
Pubmed
Wang,
Alterations of the PPP2R1B gene in human lung and colon cancer.
1998,
Pubmed
Xing,
Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins.
2006,
Pubmed
Xu,
Structure of the protein phosphatase 2A holoenzyme.
2006,
Pubmed
Yan,
Expression of active caspase-3 in mitotic and postmitotic cells of the rat forebrain.
2001,
Pubmed
Yang,
PP2A:B56epsilon is required for Wnt/beta-catenin signaling during embryonic development.
2003,
Pubmed
,
Xenbase
Zauberman,
Identification of p53 target genes through immune selection of genomic DNA: the cyclin G gene contains two distinct p53 binding sites.
1995,
Pubmed
