P53 Response In Cells Research Articles

BLIMP1 regulates cell growth through repression of p53 transcription

Tight regulation of p53 is essential for maintaining normal cell growth. Here we report that BLIMP1 acts in an autoregulatory feedback loop that controls p53 activity through repression of p53 transcription. p53 binds to and positively regulates BLIMP1, which encodes for a known B cell transcriptional repressor. Knockdown of BLIMP1 by siRNA results in both apoptosis and growth arrest in human colon cancer cells and cell-cycle arrest in primary human fibroblasts. Interestingly, the levels of both p53 mRNA and protein are substantially increased after BLIMP1 depletion, which is accompanied by the induction of p53 target genes. Importantly, the apoptosis induced by BLIMP1 depletion in HCT116 cells is largely abrogated in cells lacking p53 or in cells depleted in p53 by siRNA. We further demonstrate that BLIMP1 binds to the p53 promoter and represses p53 transcription, and this provides a mechanistic explanation for the induction of p53 response in cells depleted of BLIMP1. Hence, suppression of p53 transcription is a crucial function of endogenous BLIMP1 and is essential for normal cell growth.

High sensitivity of the ultraviolet-induced p53 response in ultraviolet-sensitive syndrome, a photosensitive disorder with a putative defect in deoxyribonucleic acid repair of actively transcribed genes

Previously, we reported a new category of photosensitive disorder named ultraviolet-sensitive syndrome (UVs S) [T. Itoh, T. Fujiwara, T. Ono, M. Yamaizumi, UVs syndrome, a new general category of photosensitive disorder with defective DNA repair, is distinct from xeroderma pigmentosum variant and rodent complementation group 1, Am. J. Hum. Genet. 56 (1995) 1267–1276.]. Cells derived from these patients show impaired recovery of RNA synthesis (RRS) after UV-irradiation irrespective of having a normal level of unscheduled DNA synthesis (UDS). These characteristics are reminiscent of Cockayne syndrome (CS) cells. By comparing sensitivity of the UV-induced p53 response in cells with different types of defects in nucleotide excision repair, we hypothesized that the UV-induced p53 response is triggered by inhibition of RNA synthesis [M. Yamaizumi, T. Sugano, UV-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle, Oncogene 9 (1994) 2775–2784.]. To test this hypothesis, we determined sensitivity of the p53 response in UVs S cells by immunostaining, Western blotting, and FACScan analysis. Maximal nuclear accumulation of p53 in the UVs S cells was observed with a one-third UV dose required for that in normal cells, while almost identical p53 responses were observed in UVs S and normal cells following treatment with heat or α-amanitin. Recovery of RNA synthesis after a low dose of UV-irradiation was impaired in UVs S cells to the same extent as seen in CS cells. These results provide further evidence to support our previous hypothesis regarding the mechanism of the p53 response induced by DNA damage.