Multiple tumor suppressor pathways negatively regulate telomerase.
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-beta pathway, mediates the TGF-beta 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.
Lin
Shiaw Yih
SY
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Elledge
Stephen J
SJ
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics*; D002460:Cell Line; D002461:Cell Line, Transformed / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005057:Eukaryotic Cells / Q000201:enzymology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D005820:Genetic Testing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074165:Zinc Finger E-box Binding Homeobox 2; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C501384:MAD1L1 protein, human; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D019098:Telomerase; D018631:ras Proteins