التفاصيل البيبلوغرافية
| العنوان: |
Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability. |
| المؤلفون: |
Lü, YiQing, Cho, Tiffany, Mukherjee, Saptaparna, Suarez, Carmen Florencia, Gonzalez-Foutel, Nicolas S, Malik, Ahmad, Martinez, Sebastien, Dervovic, Dzana, Oh, Robin Hyunseo, Langille, Ellen, Al-Zahrani, Khalid N, Hoeg, Lisa, Lin, Zhen Yuan, Tsai, Ricky, Mbamalu, Geraldine, Rotter, Varda, Ashton-Prolla, Patricia, Moffat, Jason, Chemes, Lucia Beatriz, Gingras, Anne-Claude |
| المصدر: |
Molecular Systems Biology; Jun2024, Vol. 20 Issue 6, p719-740, 22p |
| مصطلحات موضوعية: |
P53 antioncogene, MEDICAL screening, CRISPRS, PROTEIN stability, P53 protein, BREAST cancer |
| مستخلص: |
Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial 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. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer. Synopsis: Genome-wide p53 protein stability screens provide a comprehensive network view of the processes regulating wild type and mutant p53 and uncover potential targets for reinforcing wild-type p53 or targeting mutant p53 in cancer. Most proteins regulating wild-type p53 also affect mutant p53, except for p53 R337H, which harbors a distinct set of regulators. FBXO42 is a novel positive regulator for a subset of p53 mutants and collaborates with CCDC6 in regulating USP28-mediated stabilization of mutant p53. Loss of FBXO42 or CCDC6 reduces metastasis of p53 mutant pancreatic cancer cells, similar to depletion of mutant p53 itself. C16orf72/HAPSTR1 is a negative regulator affecting the stability of both wild-type and mutant p53, depending on its nuclear localization and the activity of the E3 ubiquitin ligase HUWE1. C16orf72/HAPSTR1 is a proto-oncogene and its overexpression reduces p53 levels and accelerates tumor growth in a p53 wild-type breast cancer mouse model. Genome-wide p53 protein stability screens provide a comprehensive network view of the processes regulating wildtype and mutant p53 and uncover potential targets for reinforcing wild-type p53 or targeting mutant p53 in cancer. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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