7158

TP53BP1

53BP1|p202|p53BP1;tumor protein p53 binding protein 1;TP53BP1;tumor protein p53 binding protein 1

p53-binding protein 1|tumor protein 53-binding protein, 1|tumor protein p53-binding protein, 1|tumor suppressor p53-binding protein 1

15q15-q21

protein-coding

53BP1 is a p53 binding protein of unknown function that binds to the central DNA-binding domain of p53. It relocates to the sites of DNA strand breaks in response to DNA damage and is a putative substrate of the ataxia telangiectasia-mutated (ATM) kinase. To study the biological role of 53BP1, we disrupted the 53BP1 gene in the mouse. We show that, similar to ATM(-/-) mice, 53BP1-deficient mice were growth retarded, immune deficient, radiation sensitive, and cancer prone. 53BP1(-/-) cells show a slight S-phase checkpoint defect and prolonged G(2)/M arrest after treatment with ionizing radiation. Moreover, 53BP1(-/-) cells feature a defective DNA damage response with impaired Chk2 activation. These data indicate that 53BP1 acts downstream of ATM and upstream of Chk2 in the DNA damage response pathway and is involved in tumor suppression.

The importance of the DNA damage response (DDR) pathway in development, genomic stability, and tumor suppression is well recognized. Although 53BP1 and MDC1 have been recently identified as critical upstream mediators in the cellular response to DNA double-strand breaks, their relative hierarchy in the ataxia telangiectasia mutated (ATM) signaling cascade remains controversial. To investigate the divergent and potentially overlapping functions of MDC1 and 53BP1 in the ATM response pathway, we generated mice deficient for both genes. Unexpectedly, the loss of both MDC1 and 53BP1 neither significantly increases the severity of defects in DDR nor increases tumor incidence compared with the loss of MDC1 alone. We additionally show that MDC1 regulates 53BP1 foci formation and phosphorylation in response to DNA damage. These results suggest that MDC1 functions as an upstream regulator of 53BP1 in the DDR pathway and in tumor suppression.

p53-binding protein-1 (53BP1) plays a critical role in cell cycle checkpoint and DNA repair activities. Recently, 53BP1 was recognized as a potential tumor suppressor gene. In this study, we investigated its tumor suppressor function in breast cancer. In clinical samples, we observed a lower level of 53BP1 expression in the cancer lesions than in the matched non-tumor tissues. Furthermore, the 53BP1 level showed a gradual decrease during the progression from precancerous to cancer lesion. Ectopic expression of 53BP1 can significantly inhibit cell proliferation and curb the invasiveness in breast cancer cell lines, whereas knockdown of 53BP1 by RNA interference had the opposite effects. Additionally, 53BP1 markedly inhibited xenograft formation and metastasis of breast cancer cells in nude mice. Both in vitro and in vivo studies revealed that the 53BP1 expression level was inversely correlated to the function of nuclear factor-kappaB (NF-kappaB), which contributes to the invasion and metastasis of breast cancer. Importantly, the inhibitory effect of 53BP1 on NF-kappaB activity was shown to be mediated by the upregulation of miR-146a. Together, our findings demonstrated that 53BP1 has a potent tumor suppressor activity in breast cancer, and it may serve as a novel target for breast cancer prevention and treatment.