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p53 mediates Bcl-2 phosphorylation and apoptosis via activation of the Cdc42/JNK1 pathway

Oncogene volume 19, pages 5259–5269 (2000)Cite this article

Abstract

A member of the small G protein family, cdc42, was isolated from a screen undertaken to identify p53-inducible genes during apoptosis in primary baby rat kidney (BRK) cells transformed with E1A and a temperature-sensitive mutant p53 using a PCR-based subtractive hybridization method. Cdc42 is a GTPase that belongs to the Rho/Rac subfamily of Ras-like GTPases. In response to external stimuli, Cdc42 is known to transduce signals to regulate the organization of the actin cytoskeleton, induce DNA synthesis in quiescent fibroblasts, and promote apoptosis in neuronal and immune cells. In this study, we have demonstrated that cdc42 mRNA and protein were up-regulated in the presence of wild-type p53 in BRK cells, followed by cytoplasmic to plasma membrane translocation of Cdc42. Overexpression of Cdc42 in the presence of a dominant-negative mutant p53 induced apoptosis rapidly, indicating that Cdc42 functions downstream of p53. Furthermore, stable expression of a dominant-negative mutant of Cdc42 partially inhibited p53-mediated apoptosis. The Bcl-2 family members Bcl-xL, and the adenovirus protein E1B 19K, inhibited Cdc42-mediated apoptosis, whereas Bcl-2 did not. We provide evidence that PAK1 and JNK1 may play a role downstream of Cdc42 to transduce its apoptotic signal. Cdc42/PAK1 activates JNK1-induced phosphorylation of Bcl-2, thereby inactivating its function, and that a phosphorylation resistant mutant (Bcl-2S70,87A,T56,74A) gains the ability to inhibit Cdc42- and p53-mediated apoptosis. Thus, one mechanism by which p53 promotes apoptosis is through activation of Cdc42 and inactivation of Bcl-2.

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Acknowledgements

We would like to thank Drs Alan Hall and Linda Van Aelst for cdc42 expression plasmids, Dr J Silvio Gutkind for JNK1 expression plasmid, Dr Celine Gelinas for Bcl-2 expression plasmid, and Dr Craig Thompson for Bcl-XL expression plasmid. Many thanks to Dr Andy Cuconati for making the dominant-negative PAK1 expression plasmid and all the other members of the White lab for thought-provoking discussions. This work was supported by NIH grant CA60088 and the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Center Adanced Biotechnology and Medicine, Rutgers University, 679 Hoes Lane, Room 140, Piscataway, 08854, New Jersey, NJ, USA

    Anju Thomas, Theresa Giesler & Eileen White

  2. Howard Hughes Medical Institute, Rutgers University, 679 Hoes Lane, Room 140, Piscataway, 08854, New Jersey, NJ, USA

    Theresa Giesler & Eileen White

  3. Cancer Institute of New Jersey, Rutgers University, 679 Hoes Lane, Room 140, Piscataway, 08854, New Jersey, NJ, USA

    Eileen White

  4. Department of Molecular Biology and Biochemistry, Rutgers University, 679 Hoes Lane, Room 140, Piscataway, 08854, New Jersey, NJ, USA

    Eileen White

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Thomas, A., Giesler, T. & White, E. p53 mediates Bcl-2 phosphorylation and apoptosis via activation of the Cdc42/JNK1 pathway. Oncogene 19, 5259–5269 (2000). https://doi.org/10.1038/sj.onc.1203895

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