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Molecular and Cellular Biology, July 1999, p. 5143-5154, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Mitogen-Activated Protein Kinase Kinase Kinase 1 Activates Androgen Receptor-Dependent Transcription and Apoptosis in Prostate Cancer

Maria T. Abreu-Martin,1 Ajai Chari,2,3 Andrew A. Palladino,1 Noah A. Craft,2,3 and Charles L. Sawyers2,3,*

Department of Medicine2 and Molecular Biology Institute,3 University of California at Los Angeles, and Department of Medicine, Cedars-Sinai Medical Center,1 Los Angeles, California 90095

Received 29 July 1998/Returned for modification 1 October 1998/Accepted 17 March 1999

Mitogen-activated protein (MAP) kinases phosphorylate the estrogen receptor and activate transcription from estrogen receptor-regulated genes. Here we examine potential interactions between the MAP kinase cascade and androgen receptor-mediated gene regulation. Specifically, we have studied the biological effects of mitogen-activated protein kinase kinase kinase 1 (MEKK1) expression in prostate cancer cells. Our findings demonstrate that expression of constitutively active MEKK1 induces apoptosis in androgen receptor-positive but not in androgen receptor-negative prostate cancer cells. Reconstitution of the androgen receptor signaling pathway in androgen receptor-negative prostate cancer cells restores MEKK1-induced apoptosis. MEKK1 also stimulates the transcriptional activity of the androgen receptor in the presence or absence of ligand, whereas a dominant negative mutant of MEKK1 impairs activation of the androgen receptor by androgen. These studies demonstrate an unanticipated link between MEKK1 and hormone receptor signaling and have implications for the molecular basis of hormone-independent prostate cancer growth.

* Corresponding author. Mailing address: Department of Medicine, 11-934 Factor Bldg., Box 951678, UCLA Division of Hematology-Oncology, 10833 LeConte Ave., Los Angeles, CA 90095. Phone: (310) 206-5585. Fax: (310) 206-8502. E-mail: csawyers{at}med1.medsch.ucla.edu.

Molecular and Cellular Biology, July 1999, p. 5143-5154, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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