Multiple Tumor Suppressor Pathways Negatively Regulate Telomerase

• Published in: Cell 2003-06, Vol.113 (7), p.881-889
• Main Authors: Lin, Shiaw-Yih, Elledge, Stephen J
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Polyomavirus Transforming - genetics; Antigens, Polyomavirus Transforming - metabolism; Cell Cycle Proteins; Cell Division - genetics; Cell Line; Cell Line, Transformed - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; DNA-Binding Proteins; Eukaryotic Cells - enzymology; Gene Expression Regulation, Neoplastic - genetics; Genes, Tumor Suppressor - physiology; Genetic Testing; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Neoplasm Proteins - deficiency; Neoplasm Proteins - genetics; Nuclear Proteins; Phosphoproteins - genetics; Phosphoproteins - metabolism; Proto-Oncogene Proteins; ras Proteins - genetics; ras Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA Interference; Telomerase - genetics; Telomerase - metabolism; Telomere - genetics; Telomere - metabolism; Tumor Suppressor Proteins - genetics; Zinc Finger E-box Binding Homeobox 2
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(03)00430-6

Telomerase expression is repressed in most somatic cells but is observed in stem cells and a high percentage of human cancers and has been hypothesized to contribute to tumorigenesis and maintenance of stem cell states. To explore telomerase regulation, we employed a general genetic screen to identify negative regulators of hTERT. We discovered three tumor suppressor/oncogene pathways involved in hTERT repression. One, the Mad1/c-Myc pathway, had been previously implicated in hTERT regulation. The second, SIP1, a transcriptional target of the TGF-β pathway, mediates the TGF-β regulated repression of hTERT. The third, the tumor suppressor Menin, is a direct repressor of hTERT. Depleting Menin immortalizes primary human fibroblasts and causes a transformation phenotype when coupled with expression of SV40 Large and Small T antigen and oncogenic ras. These studies suggest that multiple tumor suppressor/oncogene pathways coordinately repress hTERT expression and imply that telomerase is reactivated in human tumors through oncogenic mutations.