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Disruption of MKK4 signaling reveals its tumor-suppressor role in embryonic stem cells

Oncogene volume 23, pages 4735–4744 (2004)Cite this article

Abstract

The dual Ser/Thr kinase MKK4 and its downstream targets JNK and p38 regulate critical cellular functions during embryogenesis and development. MKK4 has been identified as a putative tumor-suppressor gene in human solid tumors of breast, prostate and pancreas. To clarify the mechanisms underlying the transforming potential of molecular defects targeting MKK4, we have generated totipotent embryonic stem (ES) cells expressing the dominant-negative mutant DN-MKK4Ala, S257A/T261A. Stably transfected DN-MKK4-ES cells exhibit a transformed fibroblast-like morphology, reduced proliferation rate, were no more submitted to cell contact inhibition, were growing in soft agar, and were much more tumorigenic than parental ES cells in athymic nude mice. These phenotypic changes: (i) are consistent with the protection of DN-MKK4-transfected ES cells from spontaneous, cell density-dependent, and stress-induced apoptosis (DAPI staining and poly (ADP-ribose) polymerase (PARP) cleavage) and (ii) correlated with alterations in JNK, p38, and Erk-1/-2 MAPK/SAPK signaling. Taken together, our data provide a new mechanism linking the MKK4 signaling pathways to cancer progression and identify MKK4 as a tumor-suppressor gene implicated in several transforming functions.

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Acknowledgements

We are indebted to Dr Allan Bradley for the AB-1 mouse ES cells, to Dr Benoit Derijard for the gift of DN-MKK4 expression vector, are grateful to Drs Fanny Bleiberg-Daniel and Ghislaine Schweizer-Groyer for critical reading of the manuscript.

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  1. Michèle Cazillis

    Present address: EPI 9935, Hôpital Robert Debré, 75019, Paris

Authors and Affiliations

  1. INSERM U.481, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, Paris, Cedex 18, 75870, France

    Michèle Cazillis, Annie-France Bringuier, Danièle Delautier, Dominique Bernuau & André Groyer

  2. INSERM U.482, Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, Paris, Cedex 12, 75571, France

    Maud Buisine & Christian Gespach

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  1. Michèle Cazillis
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Correspondence to André Groyer.

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Cazillis, M., Bringuier, AF., Delautier, D. et al. Disruption of MKK4 signaling reveals its tumor-suppressor role in embryonic stem cells. Oncogene 23, 4735–4744 (2004). https://doi.org/10.1038/sj.onc.1207619

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