Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity.
Androgen receptor regulation is pivotal for prostate growth and development. Activation of the receptor is dictated by association with androgen (ligand) and through interaction with co-activators and co-repressors. We have shown previously that cyclin D1 functions as a co-repressor to inhibit ligand-dependent androgen receptor activation. We demonstrate that cyclin D1 directly binds the N terminus of the androgen receptor and that this interaction is independent of ligand. Furthermore, we show that the interaction occurs in the nucleus and does not require the LXXLL motif of cyclin D1. Although two distinct transactivation domains exist in the N terminus (AF-1 and AF-5), the data shown support the hypothesis that cyclin D1 targets the AF-1 transactivation function. The constitutively active AF-5 domain was refractory to cyclin D1 inhibition. By contrast, cyclin D1 completely abolished androgen receptor activity, even in the presence of potent androgen receptor co-activators. This action of cyclin D1 at least partially required de-acetylase activity. Finally, we show that transient, ectopic expression of cyclin D1 results in reduced cell cycle progression in androgen-dependent LNCaP cells independent of CDK4 association. Collectively, our data support a model wherein cyclin D1 has a mitogenic (CDK4-dependent) function and an anti-mitogenic function (dependent on regulation of the AF-1 domain) that can collectively control the rate of androgen-dependent cellular proliferation. These findings provide insight into the non-cell cycle functions of cyclin D1 and provide the impetus to study its pleiotropic effects in androgen-dependent cells, especially prostatic adenocarcinomas.
Petre
Christin E
CE
Department of Cell Biology, the University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, USA.
Wetherill
Yelena B
YB
Danielsen
Mark
M
Knudsen
Karen E
KE
D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen / Q000737:chemistry / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D015533:Transcriptional Activation
D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D006655:Histone Deacetylases