Involvement of p21(WAF1/Cip1), CDK4 and Rb in activin A mediated signaling leading to hepatoma cell growth inhibition

Oncogene. 1997 Oct 2;15(14):1705-11. doi: 10.1038/sj.onc.1201348.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins
  • Carcinoma, Hepatocellular / pathology*
  • Cell Division
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / physiology*
  • Cyclins / physiology*
  • Gene Expression Regulation, Neoplastic
  • Growth Inhibitors*
  • Humans
  • Inhibins / physiology*
  • Phosphorylation
  • Proto-Oncogene Proteins*
  • Retinoblastoma Protein / physiology*
  • Signal Transduction
  • Transcription Factors / physiology
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / physiology


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Growth Inhibitors
  • Proto-Oncogene Proteins
  • Retinoblastoma Protein
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Activins
  • Inhibins
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases