气候变化领域集成服务门户(CCPortal): TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer

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DOI	10.1073/pnas.2102423118
	TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer
	Agarwal N.; Rinaldetti S.; Cheikh B.B.; Zhou Q.; Hass E.P.; Jones R.T.; Joshi M.; LaBarbera D.V.; Knott S.R.V.; Cech T.R.; Theodorescu D.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:38
英文摘要	Bladder cancer (BC) has a 70% telomerase reverse transcriptase (TERT or hTERT in humans) promoter mutation prevalence, commonly at −124 base pairs, and this is associated with increased hTERT expression and poor patient prognosis. We inserted a green fluorescent protein (GFP) tag in the mutant hTERT promoter allele to create BC cells expressing an hTERT-GFP fusion protein. These cells were used in a fluorescence-activated cell sorting-based pooled CRISPR-Cas9 Kinome knockout genetic screen to identify tripartite motif containing 28 (TRIM28) and TRIM24 as regulators of hTERT expression. TRIM28 activates, while TRIM24 suppresses, hTERT transcription from the mutated promoter allele. TRIM28 is recruited to the mutant promoter where it interacts with TRIM24, which inhibits its activity. Phosphorylation of TRIM28 through the mTOR complex 1 (mTORC1) releases it from TRIM24 and induces hTERT transcription. TRIM28 expression promotes in vitro and in vivo BC cell growth and stratifies BC patient outcome. mTORC1 inhibition with rapamycin analog Ridaforolimus suppresses TRIM28 phosphorylation, hTERT expression, and cell viability. This study may lead to hTERT-directed cancer therapies with reduced effects on normal progenitor cells. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	CRISPR-Cas9 KnockIn; HTERT; Kinome KO screening; Promoter mutation
语种	英语
scopus关键词	fusion protein; green fluorescent protein; mammalian target of rapamycin complex 1; ridaforolimus; telomerase reverse transcriptase; transcription intermediary factor 1 beta; telomerase; TERT protein, human; transcription factor; transcription intermediary factor 1 beta; TRIM28 protein, human; allele; animal experiment; animal model; Article; bladder cancer; cancer cell; cell growth; cell viability; controlled study; fluorescence activated cell sorting; gene knockout; human; human cell; in vitro study; in vivo study; mouse; nonhuman; protein expression; protein interaction; protein phosphorylation; treatment outcome; bladder tumor; cell proliferation; cell survival; gene expression regulation; genetic transcription; genetics; mutation; pathology; promoter region; stem cell; tumor cell line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Mutation; Promoter Regions, Genetic; Stem Cells; Telomerase; Transcription Factors; Transcription, Genetic; Tripartite Motif-Containing Protein 28; Urinary Bladder Neoplasms
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251017
作者单位	Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048, United States; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States; Department of Biochemistry, University of Colorado, Boulder, CO 80303, United States; BioFrontiers Institute, University of Colorado, Boulder, CO 80303, United States; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, United States; Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States; HHMI, University of Colorado, Boulder, CO 80303, United States; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
推荐引用方式 GB/T 7714	Agarwal N.,Rinaldetti S.,Cheikh B.B.,et al. TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer[J],2021,118(38).
APA	Agarwal N..,Rinaldetti S..,Cheikh B.B..,Zhou Q..,Hass E.P..,...&Theodorescu D..(2021).TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer.Proceedings of the National Academy of Sciences of the United States of America,118(38).
MLA	Agarwal N.,et al."TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer".Proceedings of the National Academy of Sciences of the United States of America 118.38(2021).