p53 isoforms Δ133p53 and p53β 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 Δ133p53 and p53β function in an endogenous regulatory mechanism for p53-mediated replicative senescence. Induced p53β and diminished Δ133p53 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 Δ133p53 induced cellular senescence, which was attributed to the regulation of p21WAF1 and other p53 transcriptional target genes. In overexpression experiments, whereas p53β cooperated with full-length p53 to accelerate cellular senescence, Δ133p53 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 p53β and reduced Δ133p53) was observed in vivo in colon adenomas with senescent phenotypes. The increased Δ133p53 and decreased p53β isoform expression found in colon carcinoma may signal an escape from the senescence barrier during the progression from adenoma to carcinoma.

[1]  Jonathan Melamed,et al.  Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence , 2008, Cell.

[2]  Izumi Horikawa,et al.  Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. , 2008, Cancer research.

[3]  Naoto Tsuchiya,et al.  Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells , 2007, Proceedings of the National Academy of Sciences.

[4]  C. Harris,et al.  Metabolism of 1,2-dimethylhydrazine by cultured human colon. , 1980, Carcinogenesis.

[5]  Michael R. Green,et al.  Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7 , 2008, Cell.

[6]  M. Yamakuchi,et al.  miR-34a repression of SIRT1 regulates apoptosis , 2008, Proceedings of the National Academy of Sciences.

[7]  L. Lim,et al.  A microRNA component of the p53 tumour suppressor network , 2007, Nature.

[8]  J. Potter,et al.  Telomere Length in the Colon Declines with Age: a Relation to Colorectal Cancer? , 2006, Cancer Epidemiology Biomarkers & Prevention.

[9]  Moshe Oren,et al.  Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. , 2007, Molecular cell.

[10]  Bas van Steensel,et al.  TRF2 Protects Human Telomeres from End-to-End Fusions , 1998, Cell.

[11]  R. Bernards,et al.  Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence , 2006, Nature Cell Biology.

[12]  J Khan,et al.  The MYCN oncogene is a direct target of miR-34a , 2008, Oncogene.

[13]  Dimitris Kletsas,et al.  Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints , 2006, Nature.

[14]  Zhenhai Zhang,et al.  p53 isoform delta113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish. , 2009, Genes & development.

[15]  T. Fojo,et al.  p53 Inhibits Hypoxia-inducible Factor-stimulated Transcription* , 1998, The Journal of Biological Chemistry.

[16]  M. Blasco,et al.  Cellular Senescence in Cancer and Aging , 2007, Cell.

[17]  John M Sedivy,et al.  Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). , 2004, Molecular cell.

[18]  Ying Feng,et al.  Supplemental Data P53-mediated Activation of Mirna34 Candidate Tumor-suppressor Genes , 2022 .

[19]  D. Peeper,et al.  Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network , 2008, Cell.

[20]  David P Lane,et al.  p53 isoforms can regulate p53 transcriptional activity. , 2005, Genes & development.

[21]  J. Shay,et al.  BLM helicase‐dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination , 2003, The EMBO journal.

[22]  George A Calin,et al.  MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. , 2008, JAMA.

[23]  W. El-Deiry,et al.  p53 downstream target genes and tumor suppression: a classical view in evolution , 2007, Cell Death and Differentiation.

[24]  N. Sharpless,et al.  Ink4a/Arf expression is a biomarker of aging. , 2004, The Journal of clinical investigation.

[25]  E. Furth,et al.  p16(INK4a) expression begins early in human colon neoplasia and correlates inversely with markers of cell proliferation. , 2000, Gastroenterology.

[26]  Robin C. Allshire,et al.  Telomere reduction in human colorectal carcinoma and with ageing , 1990, Nature.

[27]  Izumi Horikawa,et al.  Functional diversity of human protection of telomeres 1 isoforms in telomere protection and cellular senescence. , 2007, Cancer research.

[28]  Y. Furukawa,et al.  CDC20, a potential cancer therapeutic target, is negatively regulated by p53 , 2008, Oncogene.

[29]  Wenyi Wei,et al.  Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. , 1997, Science.

[30]  V. Rotter,et al.  Amyloid-β precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress , 2007, Oncogene.

[31]  M. Barbacid,et al.  Tumour biology: Senescence in premalignant tumours , 2005, Nature.

[32]  C. Harley,et al.  The telomere hypothesis of cellular aging , 1992, Experimental Gerontology.

[33]  Michael A. Beer,et al.  Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. , 2007, Molecular cell.

[34]  T. Hupp,et al.  Posttranslational Modifications of p53 in Replicative Senescence Overlapping but Distinct from Those Induced by DNA Damage , 2000, Molecular and Cellular Biology.

[35]  G. Wahl,et al.  Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles , 1992, Cell.

[36]  T. Roberts,et al.  Surveillance mechanism linking Bub1 loss to the p53 pathway , 2007, Proceedings of the National Academy of Sciences.

[37]  J. Campisi,et al.  Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation , 2004, Journal of Cell Science.

[38]  S. Lowe,et al.  Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a , 1997, Cell.

[39]  Jiri Bartek,et al.  An Oncogene-Induced DNA Damage Model for Cancer Development , 2008, Science.