Multiple Tumor Suppressor Pathways Negatively Regulate Telomerase

Cell. 2003 Jun 27;113(7):881-9. doi: 10.1016/s0092-8674(03)00430-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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*
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Telomere / genetics
  • Telomere / metabolism*
  • Tumor Suppressor Proteins / genetics*
  • Zinc Finger E-box Binding Homeobox 2
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Antigens, Polyomavirus Transforming
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • MAD1L1 protein, human
  • MEN1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2
  • Telomerase
  • ras Proteins