Abstract
Genetic studies in Caenorhabditis elegans identified lin-9 to function together with the retinoblastoma homologue lin-35 in vulva differentiation. We have now identified a human homologue of Lin-9 (hLin-9) and provide evidence about its function in the mammalian pRB pathway. hLin-9 binds to pRB and cooperates with pRB in flat cell formation in Saos-2 cells. In addition, hLin-9 synergized with pRB and Cbfal to transactivate an osteoblast-specific reporter gene. In contrast, hLin-9 was not involved in pRB-mediated inhibition of cell cycle progression or repression of E2F-dependent transactivation. Consistent with these data, hLin-9 was able to associate with partially penetrant pRB mutants that do not bind to E2F, but retain the ability to activate transcription and to promote differentiation. hLin-9 can also inhibit oncogenic transformation, dependent on the presence of a functional pRB protein. RNAi-mediated knockdown of Lin-9 can substitute for the loss of pRB in transformation of human primary fibroblasts. These data suggest that hLin-9 has tumor-suppressing activities and that the ability of hLin-9 to inhibit transformation is mediated through its association with pRB.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Caenorhabditis elegans / genetics
-
Caenorhabditis elegans Proteins / genetics
-
Cell Cycle / genetics
-
Cell Cycle / physiology
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism
-
Cell Differentiation / genetics
-
Cell Differentiation / physiology
-
Cell Line
-
Cell Shape / genetics
-
Cell Shape / physiology
-
Cell Transformation, Neoplastic / genetics
-
Cell Transformation, Neoplastic / metabolism*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
E2F Transcription Factors
-
Fibroblasts / cytology
-
Fibroblasts / metabolism
-
Humans
-
Molecular Sequence Data
-
Mutation
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism
-
Nuclear Proteins
-
Protein Binding
-
Retinoblastoma Protein / genetics
-
Retinoblastoma Protein / metabolism*
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Transcription, Genetic / genetics
-
Transcription, Genetic / physiology
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism*
Substances
-
Caenorhabditis elegans Proteins
-
Cell Cycle Proteins
-
DNA-Binding Proteins
-
E2F Transcription Factors
-
LIN-9 protein, C elegans
-
LIN9 protein, human
-
Neoplasm Proteins
-
Nuclear Proteins
-
Retinoblastoma Protein
-
Transcription Factors
-
Tumor Suppressor Proteins
-
efl-1 protein, C elegans