Abstract
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 p21WAF1/Cip1. This accumulation of p21WAF1/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 p21WAF1/Cip1 promoter. Thus, activin A, like transforming growth factor β, seems to suppress cell growth through the downstream target Rb. However, each of these cytokines seem to operate through a distinct pathway.
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Zauberman, A., Oren, M. & Zipori, D. Involvement of p21WAF1/Cip1, CDK4 and Rb in activin A mediated signaling leading to hepatoma cell growth inhibition. Oncogene 15, 1705–1711 (1997). https://doi.org/10.1038/sj.onc.1201348
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DOI: https://doi.org/10.1038/sj.onc.1201348
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