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Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-β1-induced apoptosis in human gastric cancer cells

Oncogene volume 20, pages 1254–1265 (2001)Cite this article

Abstract

Although TGF-β1, a growth inhibitor, is known to also induce apoptosis, the molecular mechanism of this apoptosis is largely undefined. Here, we identify the mechanism of TGF-β1-induced apoptosis in SNU-16 human gastric cancer cells. Cell cycle and TUNEL analysis showed that, upon TGF-β1 treatment, cells were initially arrested at the G1 phase and then driven into apoptosis. Of note, caspase-3 was activated in accordance with TGF-β1-induced G1 arrest. Activated caspase-3 is targeted to cleave p21cip1, p27kip1, and Rb, which play important roles in TGF-β-induced G1 arrest, into inactive fragments. Subsequently, Cdk2 was aberrantly activated due to the cleavage of p21 and p27. We found that the inhibition of Cdk2 activity efficiently blocks TGF-β1-induced apoptosis, whereas it did not prevent caspase-3 activation or the subsequent cleavage of target proteins. In contrast, the suppression of caspase-3 activity inhibited the cleavage of target proteins, the activation of Cdk2, and the induction of apoptosis. Taken together, our results suggest that activation of caspase-3 by TGF-β1 may initiate the conversion from G1 cell cycle arrest to apoptosis via the cleavage of p21, p27 and Rb, which in turn causes Cdk2 activation and, most significantly, Cdk2 activation as a downstream effector of caspase is a critical step for the execution of TGF-β1-induced apoptosis.

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Acknowledgements

This work was supported by the Korean Ministry of Health and Welfare Grant HMP-99-M-03-0001 and by 1999 BK21 Project for Medicine. We are grateful to EK Kim for the flow cytometric analysis and TY Kim for manuscript preparation.

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Authors and Affiliations

  1. Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-744, Korea

    Sang Gyun Kim, Hyun-Soon Jong & Yung-Jue Bang

  2. School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul, 151-742, Korea

    Sang Gyun Kim, Se Nyun Kim & Seung Hwan Hong

  3. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 110-744, Korea

    Noe Kyeong Kim & Yung-Jue Bang

  4. Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, 20892-5055, Maryland, MD, USA

    Seong-Jin Kim

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Kim, S., Kim, S., Jong, HS. et al. Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-β1-induced apoptosis in human gastric cancer cells. Oncogene 20, 1254–1265 (2001). https://doi.org/10.1038/sj.onc.1204203

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