Tumor Suppressors p53, p63TAα, p63TAy, p73α, and p73β Use Distinct Pathways to Repress Telomerase Expression

• Published in: The Journal of biological chemistry Vol. 287; no. 24; pp. 20737 - 20747
• Main Authors: Yao, Yuan, Bellon, Marcia, Shelton, Shary N., Nicot, Christophe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.06.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cancer; Cell Line; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Enzymologic - physiology; Gene Regulation; HDAC; HTLV-I; Humans; Mice; Mice, Knockout; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; p53; p63; p73; Phosphoproteins - genetics; Phosphoproteins - metabolism; Telomerase; Telomerase - biosynthesis; Telomerase - genetics; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Protein p73; Tumor Suppressor Gene; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Gene Regulation; HTLV-I; Transcription; Tumor Suppressor Gene; p63; Telomerase; p73; p53; HDAC; Cancer
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M111.319236

The promoter of the telomerase catalytic subunit (TERT) is subject to tight regulation and remains repressed in somatic cells to ensure their limited life span and to prevent tumor initiation. Here we report that the hTERT promoter is strongly repressed by p53 and the related family members p63 and p73. We found that p53-mediated repression was different in human and mouse cells and occurred through p53-dependent transcription inhibition of c-Myc or through E-box/E2F pathways, respectively. Although p63TAα-mediated repression occurred through SP1, p63TAy-mediated repression occurred through E2F signaling. Finally, p73α- and p73β-mediated repression occurred through NF-YB2. Our results show a complex multifactorial mechanism used by p53 and its family members to keep hTERT expression under tight control. Inactivation of p53 and reactivation of telomerase expression are two of the most common events in human cancer. Here we report the mechanisms used by p53, p63, and p73 to suppress telomerase expression. p53, p63, and p73 suppress telomerase expression through distinct pathways that involve E2F, E-box, c-Myc, and NF-YB. This study provides new insights into the cellular pathways used by p53, p63, and p73 to suppress hTERT expression.