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TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer.
Agarwal, Neeraj; Rinaldetti, Sebastien; Cheikh, Bassem B; Zhou, Qiong; Hass, Evan P; Jones, Robert T; Joshi, Molishree; LaBarbera, Daniel V; Knott, Simon R V; Cech, Thomas R; Theodorescu, Dan.
Afiliação
  • Agarwal N; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
  • Rinaldetti S; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048.
  • Cheikh BB; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
  • Zhou Q; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
  • Hass EP; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
  • Jones RT; Department of Biochemistry, University of Colorado, Boulder, CO 80303.
  • Joshi M; BioFrontiers Institute, University of Colorado, Boulder, CO 80303.
  • LaBarbera DV; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045.
  • Knott SRV; Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
  • Cech TR; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
  • Theodorescu D; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Article em En | MEDLINE | ID: mdl-34518220
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Transcrição Gênica / Neoplasias da Bexiga Urinária / Regiões Promotoras Genéticas / Telomerase / Proteína 28 com Motivo Tripartido / Mutação Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Transcrição Gênica / Neoplasias da Bexiga Urinária / Regiões Promotoras Genéticas / Telomerase / Proteína 28 com Motivo Tripartido / Mutação Idioma: En Ano de publicação: 2021 Tipo de documento: Article