Involvement of p21(WAF1/Cip1), CDK4 and Rb in activin A mediated signaling leading to hepatoma cell growth inhibition.
Cytokines are growth inhibitory in a target cell specific manner. The signaling pathways that characterize each cell type play a crucial role in determining the responsiveness to cytokine triggering. Activin A has been shown to suppress the growth of primary hepatocytes. Similarly, the human HepG2 hepatoma cell line was growth arrested by activin A as judged by lack of cell proliferation and suppression of DNA synthesis. In HepG2 cells activin A further induced accumulation of retinoblastoma protein in the hypophosphorylated form known to prevent entrance into S phase. This finding implies the involvement of cyclin dependent kinases and CDK inhibitors. Examination of HepG2 cells following addition of activin A revealed reduced expression of CDK4 and conversely, an increase in the CKI p21(WAF1/Cip1). This accumulation of p21(WAF1/Cip1) protein was partly due to increased transcriptional activity. Functional inactivation of p53, using a miniprotein that oligomerizes with p53 and abrogates DNA binding, abolished the ability of activin A to induce transcriptional activation from the p21(WAF1/Cip1) promoter. Thus, activin A, like transforming growth factor beta, seems to suppress cell growth through the downstream target Rb. However, each of these cytokines seem to operate through a distinct pathway.
Zauberman
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A
Department of Molecular Cell Biology, the Weizmann Institute of Science, Rehovot, Israel.
Oren
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Zipori
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D028341:Activins; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002455:Cell Division; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D016213:Cyclins / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006131:Growth Inhibitors; D006801:Humans; D007265:Inhibins / Q000502:physiology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D028341:Activins; D007265:Inhibins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases