文章基本信息

标题：p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1
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作者：Jewon Jung ; Han Liao ; Shannon A. Coker 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：7
页码：1-24
DOI：10.1016/j.isci.2021.102701
语种：English
出版社：Elsevier
摘要：SummaryInhibition of TRPML1, which is encoded byMCOLN1, is known to deter cell proliferation in various malignancies. Here, we report that the tumor suppressor, p53, repressesMCOLN1in the urothelium such that either the constitutive loss or ectopic knockdown ofTP53—in both healthy and bladder cancer cells—increasedMCOLN1expression. Conversely, nutlin-mediated activation of p53 led to the repression ofMCOLN1. ElevatedMCOLN1expression in p53-deficient cancer cells, though not sufficient for bolstering proliferation, augmented the effects of oncogenic HRAS on proliferation, cytokine production, and invasion. Our data suggest that owing to derepression ofMCOLN1, urothelial cells lacking p53 are poised for tumorigenesis driven by oncogenic HRAS. Given our prior findings thatHRASmutations predict addiction to TRPML1, this study points to the utility of TRPML1 inhibitors for mitigating the growth of a subset of urothelial tumors that lack p53.Graphical abstractDisplay OmittedHighlights•MCOLN1expression is elevated in BLCA tumors lacking p53•p53 repressesMCOLN1in both normal and transformed urothelium•MCOLN1induction upon p53 loss augmented effects of mutant HRAS•Loss of p53 andHRASmutations predict addiction to TRPML1 in bladder cancerBiological sciences; Molecular biology; Cell biology; Cancer