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J. Biol. Chem., Vol. 277, Issue 38, 35422-35433, September 20, 2002

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Identification of Human Male Germ Cell-associated Kinase, a Kinase Transcriptionally Activated by Androgen in Prostate Cancer Cells^*

Liang Xia^§, Dan Robinson, Ai-Hong Ma, Hua-Chien Chen^¶, Frederick Wu, Yun Qiu, and Hsing-Jien Kung^**

From the  Department of Biological Chemistry, School of Medicine, University of California, Davis, California 95616 and the University of California Davis Cancer Center, Sacramento, California 95817, the ^¶ National Health Research Institutes, Taipei 11529, Taiwan, and the  Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455

Androgen is involved in both normal development and malignant transformation of prostate cells. The signal transduction pathways associated with these processes are not well understood. Using a novel kinase display approach, we have identified a protein kinase, human male germ cell-associated kinase (hMAK), which is transcriptionally induced by the androgenic hormone 5-dihydrotestosterone (DHT). The kinetics of induction is rapid and dose-dependent, and the induction is not blocked by cycloheximide treatment. Real time reverse transcription-PCR studies demonstrated a 9-fold induction of hMAK by 10 nM DHT at 24 h post-stimulation. The expression levels of hMAK in prostate cancer cell lines are in general higher than those of normal prostate epithelial cells. A reverse transcription-PCR product encompassing the entire hMAK open reading frame was isolated. The results from sequencing analysis showed that the hMAK protein is 623 amino acids in length and contains a kinase catalytic domain at its N terminus, followed by a proline/glutamine-rich domain. The catalytic domain of this kinase contains sequence motifs related to both the cyclin-dependent kinase and the mitogen-activated protein kinase families. When expressed in COS1 cells, hMAK is kinase-active as demonstrated by autophosphorylation and phosphorylation of exogenous substrate and is localized in the nucleus. A 3.7-kilobase pair promoter of the hMAK locus was isolated from a human genomic DNA bacterial artificial chromosome clone and was shown to be activated by DHT. This activation can be blocked by an anti-androgen drug bicalutamide (Casodex), implicating the involvement of androgen receptor in this process. Taken together, these data suggest that hMAK is a protein kinase targeted by androgen that may participate in androgen-mediated signaling in prostate cancer cells.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF505623.

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