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Smad4-independent regulation of p21/WAF1 by transforming growth factor-β

Oncogene volume 23, pages 1043–1051 (2004)Cite this article

Abstract

The transforming growth factor-β (TGF-β)–Smad signaling pathway inhibits the growth of human epithelial cells and plays a role in tumor suppression. The Smad4 gene is mutated or deleted in 50% of pancreatic cancers. In this study, the Smad4-null pancreatic cancer cell line BxPC-3 was transfected with either the Smad4 expression vector or the empty vector and incubated in the presence or absence of TGF-β. The cells were analysed using a cDNA microarray, which included 2280 named genes to screen for target genes regulated by TGF-β in either a Smad4-dependent or -independent manner. The microarray and subsequent quantitative RT–PCR analysis demonstrated that the Smad4-independent and -dependent signaling pathways driven by TGF-β upregulated only one of the 2280 genes, respectively, suggesting that Smad4-independent signaling downstream of TGF-β might be as widespread as Smad4-dependent signaling. In this study, we demonstrated that the cyclin-dependent kinase inhibitor p21/WAF1, which has been considered the major effector of the Smad-dependent growth inhibitory signal of TGF-β, is upregulated in a Smad4-independent manner. The upregulation occurs through Smad2/3-dependent transcriptional activation of the p21/WAF1 promoter region. These results suggest a novel mechanism of gene regulation, that is, a novel signal mediator other than Smad4.

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Acknowledgements

We thank R Derynck, J Wrana, X-F Wang, J Massague, R Booher, and NE Fusenig for providing plasmids and cell lines, and Y Hikiba and M Tsubouchi for technical assistance.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Hideaki Ijichi, Motoyuki Otsuka, Keisuke Tateishi, Tsuneo Ikenoue, Takayuki Kawakami, Fumihiko Kanai, Takao Kawabe & Masao Omata

  2. Biological Technology Laboratory, Helix Research Institute, Chiba, 292-0812, Japan

    Motoyuki Otsuka & Naohiko Seki

  3. Division of Gastroenterology, The Institute for Adult Diseases, Asahi Life Foundation, Tokyo, 160-0023, Japan

    Tsuneo Ikenoue

  4. Clinical Research Center, The University of Tokyo Hospital, Tokyo, 113-8655, Japan

    Fumihiko Kanai & Yoshihiro Arakawa

  5. Pharmaceutical Division, KIRIN Brewery Co. Ltd, 3 Miyahara, Takasaki, Gunma, 370-1295, Japan

    Kiyoshi Shimizu

  6. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan

    Kohei Miyazono

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  1. Hideaki Ijichi
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Correspondence to Hideaki Ijichi.

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Ijichi, H., Otsuka, M., Tateishi, K. et al. Smad4-independent regulation of p21/WAF1 by transforming growth factor-β. Oncogene 23, 1043–1051 (2004). https://doi.org/10.1038/sj.onc.1207222

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