Abstract
Transforming growth factor-beta (TGF-beta) inhibits cell proliferation, and acquisition of TGF-beta resistance has been linked to tumorigenesis. A genetic screen was performed to identify complementary DNAs that abrogated TGF-beta sensitivity in mink lung epithelial cells. Ectopic expression of murine double minute 2 rescued TGF-beta-induced growth arrest in a p53-independent manner by interference with retinoblastoma susceptibility gene product (Rb)/E2F function. In human breast tumor cells, increased MDM2 expression levels correlated with TGF-beta resistance. Thus, MDM2 may confer TGF-beta resistance in a subset of tumors and may promote tumorigenesis by interference with two independent tumor suppressors, p53 and Rb.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Carrier Proteins*
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Cell Cycle Proteins*
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Cell Division*
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Cell Line
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Cell Transformation, Neoplastic
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DNA-Binding Proteins*
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Drug Resistance, Neoplasm
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E2F Transcription Factors
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Gene Expression
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Genes, Retinoblastoma
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Genes, p53
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Genetic Vectors
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Humans
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Mice
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Mink
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Nuclear Proteins*
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Phosphorylation
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-mdm2
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Retinoblastoma Protein / metabolism
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Retinoblastoma-Binding Protein 1
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Signal Transduction
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Transcription Factor DP1
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta / physiology
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / physiology*
Substances
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Arid4a protein, mouse
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F Transcription Factors
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Nuclear Proteins
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Proto-Oncogene Proteins
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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Transforming Growth Factor beta
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2