Abstract
Although it has been demonstrated that p21WAF1/Cip1 could be induced by transforming growth factor-β1 (TGF-β1) in a Smad-dependent manner, the cross-talk of Smad signaling pathway with other signaling pathways still remains poorly understood. In this study, we investigated a possible role of protein kinase C (PKC) signaling pathway in TGF-β1 induction of p21WAF1/Cip1 in human keratinocytes HaCaT cells. Our data show that PKC is required for TGF-β1 induction of p21WAF1/Cip1 as evidenced by the fact that specific inhibition of PKC leads to a decrease in p21WAF1/Cip1 protein and mRNA expression induced by TGF-β1. And this notion is further supported by the observation that activation of p21WAF1/Cip1 promoter activity is dramatically attenuated by treatment with PKC inhibitor. However, PKC signaling pathway is not associated with TGF-β1 activation of Smad signaling pathway, because inhibition of PKC signaling pathway does not affect nuclear translocation of Smads induced by TGF-β1. Taken together, our data suggest that PKC signaling pathway is required for 21WAF1/Cip1 expression by TGF-β1, which is independent of Smad signaling pathway.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- TGF-β:
-
transforming growth factor-β
- PKC:
-
protein kinase C
- PDBu:
-
phorbol dibutyrate
References
Blanchette, F., Rivard, N., Rudd, P., Grondin, F., Attisano, L., and Dubois, C. M., Cross-talk between the p42/p44 MAP kinase and Smad pathways in transforming growth factor beta 1-induced furin gene transactivation.J. Biol. Chem., 276, 33986–33994 (2001).
Datto, M. B., Li, Y., Panus, J. F., Howe, D. J., Xiong, Y., and Wang, X. F., Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53- independent mechanism.Proc. Natl. Acad. Sci. U.S.A., 92, 5545–5549 (1995).
de Caestecker, M. P., Piek, E., and Roberts, A. B., Role of transforming growth factor-beta signaling in cancer.J. Natl. Cancer Inst., 92, 1388–1402 (2000).
Derynck, R. and Feng, X. H., TGF-beta receptor signaling.Biochim. Biophys. Acta., 1333, F105-F150 (1997).
Derynck, R. and Zhang, Y. E., Smad-dependent and Smad- independent pathways in TGF-beta family signalling.Nature, 425, 577–584 (2003).
Derynck, R., Gelbart, W. M., Harland, R. M., Heldin, C. H., Kern, S. E., Massague, J., Melton, D. A., Mlodzik, M., Padgett, R. W., Roberts, A. B., Smith, J., Thomsen, G. H., Vogelstein, B., and Wang, X. F., Nomenclature: vertebrate mediators of TGF-beta family signals.Cell, 87, 173 (1996).
Han, J. W., Ahn, S. H., Kim, Y. K., Bae, G. U., Yoon, J. W., Hong, S., Lee, H. Y., Lee, Y. W., and Lee, H. W., Activation of p21(WAF1/Cip1) transcription through Sp1 sites by histone deacetylase inhibitor apicidin: involvement of protein kinase C.J. Biol. Chem., 276, 42084–42090 (2001).
Hu, P. P., Shen, X., Huang, D., Liu, Y., Counter, C., and Wang, X. F., The MEK pathway is required for stimulation of p21(WAF1/CIP1) by transforming growth factor-beta.J. Biol. Chem., 274, 35381–35387 (1999).
Itoh, S., Itoh, F., Goumans, M. J., and Ten Dijke, P., Signaling of transforming growth factor-beta family members through Smad proteins.Eur. J. Biochem., 267, 6954–6967 (2000).
Kamaraju, A. K. and Roberts, A. B., Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cellsin vivo.J. Biol. Chem., 280, 1024–1036 (2005).
Kim, Y. K., Bae, G. U., Kang, J. K., Park, J. W., Lee, E. K., Lee, H. Y., Choi, W. S., Lee, H. W., and Han, J. W., Cooperation of H2O2-mediated ERK activation with Smad pathway in TGF- beta1 induction of p21WAF1/Cip1.Cell Signal., 18, 236–243 (2006).
Kim, Y. K., Han, J. W., Woo, Y. N., Chun, J. K., Yoo, J. Y., Cho, E. J., Hong, S., Lee, H. Y., Lee, Y. W., and Lee, H. W., Expression of p21(WAF1/Cip1) through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase-PKC epsilon signaling pathway.Oncogene, 22, 6023–6031 (2003).
Li, C. Y., Suardet, L., and Little, J. B., Potential role of WAF1/ Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect.J. Biol. Chem., 270, 4971–4974 (1995).
Massague, J., TGF-beta signal transduction.Annu. Rev. Biochem. 67, 753–791 (1998).
Roberts, A. B., Molecular and cell biology of TGF-beta.Miner. Electrolyte Metab. 24, 111–119 (1998).
Savage, C., Das, P., Finelli, A. L., Townsend, S. R., Sun, C. Y., Baird, S. E., and Padgett, R. W.,Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components.Proc. Natl. Acad. Sci. U.S.A., 93, 790–794 (1996).
Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H., and Gelbart, W. M., Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function inDrosophila melanogaster.Genetics, 139, 1347–1358 (1995).
Sherr, C. J. and Roberts, J. M., Inhibitors of mammalian G1 cyclin-dependent kinases.Genes Dev., 9, 1149–1163 (1995).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kim, Y.K. TGF-β1 induction of p21WAF1/cip1 requires smad-independent protein kinase C signaling pathway. Arch Pharm Res 30, 739–742 (2007). https://doi.org/10.1007/BF02977636
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02977636