TY - JOUR
T1 - Multiple tumor suppressor pathways negatively regulate telomerase
AU - Lin, Shiaw Yih
AU - Elledge, Stephen J.
N1 - Funding Information:
We thank R.A. Weinberg, W. Hanh, Z. Songyang, T. de Lange, J. Shay, A. Levine, R. Depinho, A. Burns, D.C. Dean, and T.K. Kim for gifts of reagents and helpful discussions. We also thank Kaiyi Li for the technical support on TRF assay. This work was supported by an NIH fellowship (1 F32 CA93943) to S.-Y.L. S.J.E. is a Senior Scholar of the Ellison Foundation and an Investigator with the Howard Hughes Medical Institute and the Welch Professor of Biochemistry.
PY - 2003/6/27
Y1 - 2003/6/27
N2 - 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.
AB - 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.
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U2 - 10.1016/S0092-8674(03)00430-6
DO - 10.1016/S0092-8674(03)00430-6
M3 - Article
C2 - 12837246
AN - SCOPUS:0037821661
SN - 0092-8674
VL - 113
SP - 881
EP - 889
JO - Cell
JF - Cell
IS - 7
ER -