p53 isoforms Delta133p53 and p53beta are endogenous regulators of replicative cellular senescence.
The finite proliferative potential of normal human cells leads to replicative cellular senescence, which is a critical barrier to tumour progression in vivo. We show that the human p53 isoforms Delta133p53 and p53beta function in an endogenous regulatory mechanism for p53-mediated replicative senescence. Induced p53beta and diminished Delta133p53 were associated with replicative senescence, but not oncogene-induced senescence, in normal human fibroblasts. The replicatively senescent fibroblasts also expressed increased levels of miR-34a, a p53-induced microRNA, the antisense inhibition of which delayed the onset of replicative senescence. The siRNA (short interfering RNA)-mediated knockdown of endogenous Delta133p53 induced cellular senescence, which was attributed to the regulation of p21(WAF1) and other p53 transcriptional target genes. In overexpression experiments, whereas p53beta cooperated with full-length p53 to accelerate cellular senescence, Delta133p53 repressed miR-34a expression and extended the cellular replicative lifespan, providing a functional connection of this microRNA to the p53 isoform-mediated regulation of senescence. The senescence-associated signature of p53 isoform expression (that is, elevated p53beta and reduced Delta133p53) was observed in vivo in colon adenomas with senescent phenotypes. The increased Delta133p53 and decreased p53beta isoform expression found in colon carcinoma may signal an escape from the senescence barrier during the progression from adenoma to carcinoma.
Fujita
Kaori
K
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258, USA.
Mondal
Abdul M
AM
Horikawa
Izumi
I
Nguyen
Giang H
GH
Kumamoto
Kensuke
K
Sohn
Jane J
JJ
Bowman
Elise D
ED
Mathe
Ewy A
EA
Schetter
Aaron J
AJ
Pine
Sharon R
SR
Ji
Helen
H
Vojtesek
Borivoj
B
Bourdon
Jean-Christophe
JC
Lane
David P
DP
Harris
Curtis C
CC
D045744:Cell Line, Tumor; D016922:Cellular Senescence; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53
Cell. 1997 Mar 7;88(5):593-602
9054499
Hum Mol Genet. 1995 Feb;4(2):313-4
7757087
Cell Death Differ. 2007 Jan;14(1):3-9
17068503
Exp Gerontol. 1992 Jul-Aug;27(4):375-82
1459213
Cell. 2007 Jul 27;130(2):223-33
17662938
Nature. 2005 Aug 4;436(7051):642
16079833
Science. 2008 Mar 7;319(5868):1352-5
18323444
Gastroenterology. 2000 Oct;119(4):929-42
11040180
Oncogene. 2007 Nov 15;26(52):7302-12
17533371
Oncogene. 2008 Sep 4;27(39):5204-13
18504438
J Cell Sci. 2005 Feb 1;118(Pt 3):485-96
15657080
Mol Cell. 2004 May 21;14(4):501-13
15149599
Cancer Res. 2008 May 1;68(9):3193-203
18451145
Genes Dev. 2009 Feb 1;23(3):278-90
19204115
Mol Cell. 2007 Jun 8;26(5):745-52
17540599
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13421-6
18755897
Proc Natl Acad Sci U S A. 2007 May 15;104(20):8334-9
17488820
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15472-7
17875987
Nature. 1990 Aug 30;346(6287):866-8
2392154
Oncogene. 2008 Mar 6;27(11):1562-71
17873905
Cell. 2008 Jun 13;133(6):1019-31
18555778
Mol Cell. 2007 Jun 8;26(5):731-43
17540598
Science. 1997 Aug 8;277(5327):831-4
9242615
Nat Cell Biol. 2006 Aug;8(8):877-84
16862142
Cell. 1992 Sep 18;70(6):937-48
1525830
Curr Biol. 2007 Aug 7;17(15):1298-307
17656095
Cell. 2008 Jun 13;133(6):1006-18
18555777
JAMA. 2008 Jan 30;299(4):425-36
18230780
J Biol Chem. 1998 May 15;273(20):11995-8
9575138
Genes Dev. 2005 Sep 15;19(18):2122-37
16131611
Cell. 1998 Feb 6;92(3):401-13
9476899
Cell. 2008 Feb 8;132(3):363-74
18267069
J Clin Invest. 2004 Nov;114(9):1299-307
15520862
Mol Cell Biol. 2000 Apr;20(8):2803-8
10733583
Nature. 2006 Nov 30;444(7119):633-7
17136093
Cancer Epidemiol Biomarkers Prev. 2006 Mar;15(3):573-7
16537718
Nature. 2007 Jun 28;447(7148):1130-4
17554337
EMBO J. 2003 Mar 3;22(5):1210-22
12606585
Carcinogenesis. 1980 May;1(5):375-80
7273277
Cancer Res. 2007 Dec 15;67(24):11677-86
18089797