p53 plays critical roles in tumor suppression, stem cell functions and aging in vivo. Our laboratory continues to study clinical significance of cancer-associated p53 mutations and biological activities of specific mutations (e.g., Arg-to-Ser mutation at codon 249). Our recent focus has been on functional interactions between p53 and the telomere-capping protein complex (called shelterin), which protects telomeres from initiating unwanted DNA damage response. Uncapped, dysfunctional telomeres at the end of cellular replicative lifespan lose this protective mechanism and trigger telomere-initiated DNA damage signaling to activate p53 and thereby induce replicative senescence. We have identified a signaling pathway involving p53, Siah-1 (a p53-inducible E3 ubiquitin ligase) and TRF2 (a component of the shelterin complex). Endogenous TRF2 and Siah-1 were down- and up-regulated, respectively, at replicative senescence with physiologically activated p53. Allelic loss, shRNA knockdown, dominant-negative inhibition by a natural p53 isoform (delta133p53), nutlin-3a activation and overexpression of p53 all showed that p53 induced Siah-1 and repressed TRF2. The p53-dependent proteasomal degradation of TRF2 was attributed to the E3 ligase activity of Siah-1 to ubiquitinate TRF2. siRNA knockdown of Siah-1 stabilized TRF2 protein and extended the cellular replicative lifespan. This study thus suggests that the p53, Siah-1 and TRF2 constitute a novel signaling pathway that regulates p53-mediated cellular senescence by co-operating with the previously identified downstream pathways involving miR-34a and p21WAF1. Most importantly, p53, a downstream effector of the damage signaling from uncapped telomeres, has been shown to also function upstream of the telomere-capping protein complex, suggesting the presence of a positive feedback loop that orchestrates the telomere-initiated DNA damage signaling to cellular senescence. Our ongoing project has also made significant contribution to collaborative studies including: identification of miR-22 as a novel p53 target that controls p21WAF1 expression and cell fate decision (i.e., apoptosis vs. cellular senescence);and discovery of stem cell-like gene expression traits associated with p53 mutations in hepatocellular carcinoma, which prompts further investigation of the roles of p53 in cancer and normal stem cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Tang, Y; Horikawa, I; Ajiro, M et al. (2012) Downregulation of splicing factor SRSF3 induces p53ýý, an alternatively spliced isoform of p53 that promotes cellular senescence. Oncogene :
Schetter, Aaron J; Harris, Curtis C (2012) Tumor suppressor p53 (TP53) at the crossroads of the exposome and the cancer genome. Proc Natl Acad Sci U S A 109:7955-6
Tsuchiya, Naoto; Izumiya, Masashi; Ogata-Kawata, Hiroko et al. (2011) Tumor suppressor miR-22 determines p53-dependent cellular fate through post-transcriptional regulation of p21. Cancer Res 71:4628-39
Horikawa, Izumi; Fujita, Kaori; Harris, Curtis C (2011) p53 governs telomere regulation feedback too, via TRF2. Aging (Albany NY) 3:26-32
Woo, Hyun Goo; Wang, Xin Wei; Budhu, Anuradha et al. (2011) Association of TP53 mutations with stem cell-like gene expression and survival of patients with hepatocellular carcinoma. Gastroenterology 140:1063-70
Fujita, Kaori; Horikawa, Izumi; Mondal, Abdul M et al. (2010) Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence. Nat Cell Biol 12:1205-12
Jiang, Weidong; Wang, Xin Wei; Unger, Tamar et al. (2010) Cooperation of tumor-derived HBx mutants and p53-249(ser) mutant in regulating cell proliferation, anchorage-independent growth and aneuploidy in a telomerase-immortalized normal human hepatocyte-derived cell line. Int J Cancer 127:1011-20
Robles, Ana I; Harris, Curtis C (2010) Clinical outcomes and correlates of TP53 mutations and cancer. Cold Spring Harb Perspect Biol 2:a001016
Simone, Nicole L; Soule, Benjamin P; Ly, David et al. (2009) Ionizing radiation-induced oxidative stress alters miRNA expression. PLoS One 4:e6377
Zeng, Sicong; Xiang, Tao; Pandita, Tej K et al. (2009) Telomere recombination requires the MUS81 endonuclease. Nat Cell Biol 11:616-23

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