Brian Lehmann
Last active: 9/15/2015

Distinct roles for p107 and p130 in Rb-independent cellular senescence.

Lehmann BD, Brooks AM, Paine MS, Chappell WH, McCubrey JA, Terrian DM
Cell Cycle. 2008 7 (9): 1262-8

PMID: 18418057 · PMCID: PMC3474322 · DOI:10.4161/cc.7.9.5945

Telomere attrition, DNA damage and constitutive mitogenic signaling can all trigger cellular senescence in normal cells and serve as a defense against tumor progression. Cancer cells may circumvent this cellular defense by acquiring genetic mutations in checkpoint proteins responsible for regulating permanent cell cycle arrest. A small family of tumor suppressor genes encoding the retinoblastoma susceptibility protein family (Rb, p107, p130) exerts a partially redundant control of entry into S phase of DNA replication and cellular proliferation. Here we report that activation of the p53-dependent DNA damage response has been found to accelerate senescence in human prostate cancer cells lacking a functional Rb protein. This novel form of irradiation-induced premature cellular senescence reinforces the notion that other Rb family members may compensate for loss of Rb protein in the DNA damage response pathway. Consistent with this hypothesis, depletion of p107 potently inhibits the irradiation-induced senescence observed in DU145 cells. In contrast, p130 depletion triggers a robust and unexpected form of premature senescence in unirradiated cells. The dominant effect of depleting both p107 and p130, in the absence of Rb, was a complete blockade of irradiation-induced cellular senescence. Onset of the p107-dependent senescence was temporally associated with p53-mediated stabilization of the cyclin-dependent kinase inhibitor p27 and decreases in c-myc and cks1 expression. These results indicate that p107 is required for initiation of accelerated cellular senescence in the absence of Rb and introduces the concept that p130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele.

MeSH Terms (17)

Carcinoma Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic Cellular Senescence Crk-Associated Substrate Protein Cyclin-Dependent Kinase Inhibitor p27 DNA Damage Down-Regulation Genes, cdc Humans Male Prostatic Neoplasms Radiation Retinoblastoma-Like Protein p107 Retinoblastoma Protein Tumor Suppressor Proteins

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