Yin Yang 1 Promotes p53 Degradation

Abstract

Yin yang 1 (YY1) is a transcriptional regulator, and knockout of this protein in mice causes embryonic death at the time of implantation, a stage when there is rapid cell proliferation. Sui et al. used cultured cells to study the mechanism by which YY1 may regulate cell proliferation and found that chicken DT40 cells with only one functional allele of YY1 showed compromised proliferation, and homozygous knockout cells showed characteristics of apoptosis. In both the DT40 cells and mammalian cultured cells, the decrease in YY1 was associated with an increase in the amount of the tumor suppressor and transcriptional regulator p53 and increased abundance of p53 targets. Analysis of the ability of mutants of YY1 lacking various domains to rescue the proliferation defect indicated that the transcriptional regulatory activity of YY1 was dispensable for this proliferation-stimulating function. Using in vitro assays and immunoprecipitation assays with lysates from cultured cells, YY1 was found to interact with both p53 and its negative regulator Hdm2 (the human homolog of the mouse E3 ligase Mdm2). In cells deficient in YY1, p53 ubiquitination was decreased, and, in cells overexpressing YY1, the abundance of p53 decreased through a mechanism independent of DNA-binding activity of YY1, an effect that required active Hdm2. Furthermore, an interaction between the Hdm2 inhibitor p14 ARF and YY1 was also detected by coimmunoprecipitation and these two proteins (p14 ARF and YY1) appear to compete for interaction with Hdm2. Thus, the effect of YY1 on cell proliferation appears to be mediated by its ability to stimulate the degradation of p53, thus preventing p53-mediated growth arrest and apoptosis. G. Sui, E. B. Affar, Y. Shi, C. Brignone, N. R. Wall, P. Yin, M. Donohoe, M. P. Luke, D. Calvo, S. R. Grossman, Y. Shi, Yin yang 1 is a negative regulator of p53. Cell 117 , 859-872 (2004). [Online Journal]