突变体
生物
调节器
野生型
基因
癌变
清脆的
抑制器
细胞生物学
遗传学
癌症研究
作者
YiQing Lü,Tiffany Cho,Saptaparna Mukherjee,Ahmad Malik,Nicolás Sebastián González Foutel,Robin H. Oh,Ellen Langille,Khalid N. Al-Zahrani,Zhen Yuan Lin,Varda Rotter,Patrícia Ashton‐Prolla,Lucía B. Chemes,Jason Moffat,Anne‐Claude Gingras,Moshe Oren,Daniel Durocher,Daniel Schramek
标识
DOI:10.1101/2022.03.13.483372
摘要
Abstract Tumour suppressor p53 ( TP53 ) is the most frequently mutated gene in cancer. Several hotspot p53 mutants not only lose tumour suppressive capabilities, but also function in a dominant-negative manner, suppressing canonical wild-type p53 function. Furthermore, some hotspot p53 mutants promote oncogenesis by gain-of-function mechanisms. Levels of p53 are regulated predominantly through regulation of protein stability and while wild-type p53 is normally kept at very low levels at steady-state, p53 mutants are often stabilized in tumours, which may be vital for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. We found that most proteins that regulate wild-type p53 also regulate a subset of p53 mutants with the exception of p53 R337H regulators, which are largely private to this mutant. Mechanistically, we identified FBXO42 as a novel positive regulator of a subset of p53 mutants comprising R273H, R248Q and R248W. We show that FBXO42 acts together with CCDC6 to regulate USP28-mediated p53 stabilization. Our work also identifies C16orf72 as a negative regulator of the stability of wild-type p53 and of all p53 mutants tested. C16orf72 is amplified in breast cancer, and we show that C16orf72 regulates p53 levels in mammary epithelium of mice and its overexpression results in accelerated breast cancer with reduced p53 levels. Together, this work provides a network view of the processes that regulate p53 stability, which might provide clues for reinforcing wild-type p53 or targeting mutant p53 in cancer.
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