title: Multiple tumor suppressor pathways negatively regulate telomerase.
abstract: 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.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Shiaw Yih
authors.initials: SY
authors.lastname: Lin
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: 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
chemical_list: 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