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J Biol Chem, Vol. 273, Issue 32, 20213-20222, August 7, 1998

Multiple G₁ Regulatory Elements Control the Androgen-dependent Proliferation of Prostatic Carcinoma Cells

Karen E. Knudsen, Karen C. Arden^§, and Webster K. Cavenee^§¶

From the  Ludwig Institute for Cancer Research, the ^§ Department of Medicine, the ^¶ Center for Molecular Genetics, and the  Cancer Center, University of California at San Diego, La Jolla, California 92093-0660

Prostatic epithelial cells and most primary prostate tumors are dependent on androgen for growth, but how androgen regulates cellular proliferation remains unsolved. Using poorly understood mechanisms, recurrent tumor cells evade the androgen requirement. We utilized androgen-dependent prostatic tumor cells to demonstrate that androgen exerts its effect on the cell cycle by influencing specific aspects of G₁-S progression. Androgen depletion of these cells results in early G₁ arrest, characterized by reduced cyclin-dependent kinase activity, and underphosphorylated retinoblastoma tumor suppressor protein (RB). The reduction in kinase activity was partially attributed to reduction of specific G₁ cyclins and alternate regulation of cyclin-dependent kinase inhibitors. Using this information, we developed a reliable assay to assess the ability of specific G₁ regulatory proteins to circumvent these controls and promote androgen-independent growth. As expected, inactivation of RB was required for progression through the cell cycle. Surprisingly, overexpression of G₁ cyclins, which drives RB phosphorylation, was insufficient to promote androgen-independent cell cycle progression. Introduction of viral oncoproteins did promote G₁-S progression in the absence of androgen, dependent on their ability to sequester RB and related proteins. These results provide the first evidence that multiple elements governing the G₁-S transition dictate androgen-dependent growth, and the formation of androgen-independent prostatic tumors may be because of misregulation of these processes.

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