PP2A:B56{epsilon}, a substrate of caspase-3, regulates p53-dependent and p53-independent apoptosis during development.
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.
Jin
Zhigang
Z
Department of Pediatrics, Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, Ohio 43205, USA.
Wallace
Lindsay
L
Harper
Scott Q
SQ
Yang
Jing
J
D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019521:Body Patterning / Q000502:physiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000196:embryology*; D047108:Embryonic Development / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D054259:Neural Tube / Q000196:embryology*; D020641:Polymorphism, Single Nucleotide; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D016159:Tumor Suppressor Protein p53; D029867:Xenopus Proteins; D054648:Protein Phosphatase 2; D053148:Caspase 3
J Biol Chem. 2007 Jan 5;282(1):573-80
17085438
Dev Biol. 1987 Feb;119(2):560-78
3803718
Oncogene. 1993 Aug;8(8):2159-66
8336941
J Biol Chem. 1995 Nov 3;270(44):26123-8
7592815
Int J Cancer. 2001 Sep;93(6):798-804
11519040
Proc Natl Acad Sci U S A. 1990 Oct;87(19):7555-9
1699228
Biochem Pharmacol. 2003 Oct 15;66(8):1453-8
14555221
Nat Rev Cancer. 2002 Aug;2(8):594-604
12154352
J Biol Chem. 2006 Aug 11;281(32):23003-12
16717086
J Biol Chem. 2002 Jul 26;277(30):27449-67
11956189
Cancer Metastasis Rev. 2008 Jun;27(2):137-46
18214640
Science. 2002 Dec 6;298(5600):1912-34
12471243
Science. 1998 Oct 9;282(5387):284-7
9765152
J Biol Chem. 2008 Dec 19;283(51):35474-85
18957415
Mol Cell Proteomics. 2007 Feb;6(2):319-32
17121811
Mol Cell Biol. 2008 Jan;28(1):448-56
17967874
Cell Death Differ. 2010 Jan;17(1):158-69
19680261
Development. 1997 Aug;124(16):3185-95
9272959
J Biol Chem. 2001 Jun 8;276(23):20633-40
11279218
Cell Death Differ. 1998 Sep;5(9):774-84
10200537
EMBO J. 2007 Jan 24;26(2):402-11
17245430
Cytogenet Cell Genet. 1995;69(3-4):190-2
7698009
Cell. 2006 Oct 20;127(2):341-53
17055435
J Exp Med. 1999 Dec 20;190(12):1879-90
10601362
Curr Opin Cell Biol. 2006 Dec;18(6):623-31
17030123
Biochim Biophys Acta. 2009 Jan;1795(1):1-15
18588945
J Comp Neurol. 2001 Apr 23;433(1):4-22
11283945
Exp Cell Res. 1998 Oct 10;244(1):302-9
9770373
Curr Opin Cell Biol. 2002 Dec;14(6):721-6
12473345
Dev Biol. 1997 Sep 15;189(2):335-46
9299125
J Biol Chem. 1997 May 23;272(21):13459-62
9153186
Clin Cancer Res. 2009 Oct 1;15(19):6301-8
19773383
Cell Cycle. 2007 Oct 1;6(19):2377-85
17700073
Trends Biochem Sci. 1997 Jul;22(7):245-51
9255065
Genome Dyn. 2006;1:131-148
18724058
Cell. 2007 Jun 1;129(5):969-82
17540176
Genes Cells. 2002 Aug;7(8):869-80
12167164
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4221-6
11904383
J Virol. 2001 Oct;75(19):9142-55
11533178
Dev Cell. 2009 Sep;17(3):303-5
19758553
Biochem J. 2001 Feb 1;353(Pt 3):417-39
11171037
Mol Cell. 2002 Apr;9(4):761-71
11983168
Proc Natl Acad Sci U S A. 1988 Mar;85(6):1768-71
3126494
J Biol Chem. 2006 Apr 28;281(17):11515-22
16495229
Nature. 2009 Apr 30;458(7242):1127-30
19407794
J Biol Chem. 2009 Mar 13;284(11):7190-200
19129191
Cell. 2009 Oct 30;139(3):468-84
19879837
Mol Cell Biol. 2002 Jun;22(11):3674-84
11997504
Blood. 2002 Aug 15;100(4):1310-7
12149212
Anal Chem. 2009 Jun 1;81(11):4493-501
19413330
Oncogene. 2005 Nov 21;24(52):7746-55
16299534
Mol Cell. 2009 Mar 13;33(5):537-45
19285938
Adv Cancer Res. 2001;82:55-84
11447765
Dev Biol. 1998 Nov 1;203(1):36-48
9806771
Cell. 2007 Jul 13;130(1):21-4
17632053
Oncogene. 2001 Apr 5;20(15):1892-9
11313937
Mech Dev. 1997 Dec;69(1-2):183-95
9486540
Mol Cell Biol. 1996 Nov;16(11):6593-602
8887688
Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11025-30
12177420
Cell Cycle. 2008 Jan 1;7(1):3-6
18196968
Annu Rev Biochem. 2004;73:87-106
15189137
Oncogene. 2009 Feb 5;28(5):721-33
19029949
PLoS Biol. 2007 Aug;5(8):e202
17608567
Cell Adh Migr. 2007 Jul-Sep;1(3):140-1
19262135
Science. 2010 Jan 8;327(5962):172-7
19965387
Cell. 2006 Dec 15;127(6):1239-51
17174897
Development. 2003 Dec;130(23):5569-78
14522869
Dev Biol. 2007 Feb 15;302(2):477-93
17074314
Genes Dev. 1995 May 15;9(10):1164-76
7758942
Bioessays. 2006 Aug;28(8):775-9
16927389
Oncogene. 1995 Jun 15;10(12):2361-6
7784084
Nature. 2007 Jan 4;445(7123):53-7
17086192
J Biol Chem. 1996 May 10;271(19):11059-62
8626647
Cell. 2003 May 2;113(3):301-14
12732139
Biochim Biophys Acta. 2009 May;1787(5):414-20
19007744
Cancer Res. 2005 Sep 15;65(18):8183-92
16166293
Oncogene. 2001 Jan 4;20(1):10-5
11244497