The androgen receptor (AR), when complexed with 5␣-dihydrotestosterone (DHT), supports the survival and proliferation of prostate cells, a process critical for normal development, benign prostatic hypertrophy, and tumorigenesis. However, the androgen-responsive genetic pathways that control prostate cell division and differentiation are largely unknown. To identify such pathways, we examined gene expression in the ventral prostate 6 and 24 h after DHT administration to androgen-depleted rats. 234 transcripts were expressed significantly differently from controls (p < 0.05) at both time points and were subjected to extensive data mining. Functional clustering of the data reveals that the majority of these genes can be classified as participating in induction of secretory activity, metabolic activation, and intracellular signaling/signal transduction, indicating that AR rapidly modulates the expression of genes involved in proliferation and differentiation in the prostate. Notably AR represses the expression of several key cell cycle inhibitors, while modulating members of the wnt and notch signaling pathways, multiple growth factors, and peptide hormone signaling systems, and genes involved in MAP kinase and calcium signaling. Analysis of these data also suggested that p53 activity is negatively regulated by AR activation even though p53 RNA was unchanged. Experiments in LNCaP prostate cancer cells reveal that AR inhibits p53 protein accumulation in the nucleus, providing a post-transcriptional mechanism by which androgens control prostate cell growth and survival. In summary these data provide a comprehensive view of the earliest events in AR-mediated prostate cell proliferation in vivo, and suggest that nuclear exclusion of p53 is a critical step in prostate growth.

The orphan nuclear receptor Nurr1 is essential for the development and maintenance of midbrain dopaminergic neurons, the cells that degenerate during Parkinson's disease, by promoting the transcription of genes involved in dopaminergic neurotransmission. Since Nurr1 lacks a classical ligand-binding pocket, it is not clear which factors regulate its activity and how these factors are affected during disease pathogenesis. Since Wnt signaling via ␤-catenin promotes the differentiation of Nurr1؉ dopaminergic precursors in vitro, we tested for functional interactions between these systems. We found that ␤-catenin and Nurr1 functionally interact at multiple levels. In the absence of ␤-catenin, Nurr1 is associated with Lef-1 in corepressor complexes. ␤-Catenin binds Nurr1 and disrupts these corepressor complexes, leading to coactivator recruitment and induction of Wnt-and Nurr1-responsive genes. We then identified KCNIP4/calsenilin-like protein as being responsive to concurrent activation by Nurr1 and ␤-catenin. Since KCNIP4 interacts with presenilins, the Alzheimer's disease-associated proteins that promote ␤-catenin degradation, we tested the possibility that KCNIP4 induction regulates ␤-catenin signaling. KCNIP4 induction limited ␤-catenin activity in a presenilindependent manner, thereby serving as a negative feedback loop; furthermore, Nurr1 inhibition of ␤-catenin activity was absent in PS1 ؊/؊ cells or in the presence of small interfering RNAs specific to KCNIP4. These data describe regulatory convergence between Nurr1 and ␤-catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling.Expression and maintenance of the dopaminergic phenotype in the ventral midbrain (VM) require the orphan nuclear receptor (NR) Nurr1 (NR4A2) (48,59). Genetic ablation of Nurr1 produces embryonic lethality due to a nearly complete absence specifically of mesencephalic dopaminergic neurons, which are critical for motor function. Nurr1 regulates both the differentiation and the maintenance of these dopaminergic cells, as Nurr1 ϩ/Ϫ mice appear normal at birth but develop motor deficits resulting from reduced numbers of dopaminergic neurons and lower dopamine levels in the striatum (22). At the molecular level, Nurr1 binds specific response elements in the promoters of genes involved in dopaminergic neurotransmission, such as the genes encoding tyrosine hydroxylase (TH), L-aromatic amino acid decarboxylase, and the dopamine transporter (20,26,44,45). In Parkinson's disease, mesencephalic dopaminergic neurons degenerate, ultimately leading to severe motor deficits; correspondingly, Nurr1 levels appear to be reduced (10, 11). Therapeutic strategies that promote Nurr1 function in Parkinson's disease might therefore restore dopaminergic function or even increase the number of dopaminergic neurons. However, Nurr1 has a closed ligand-binding pocket and thus appears to be regulated by ligand-independent mechanisms (55). These mechanisms include changes in the expression of its RNA and protein (36,47,54) and changes by seco...

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Androgens increase muscle mass, decrease fat mass, and reduce high-density lipoprotein cholesterol (HDL), but the relationship between body composition, lipoprotein metabolism, and androgens has not been explained. Here we treated ovariectomized cynomolgus monkeys with 5alpha-dihydrotestosterone (DHT) or vehicle for 14 d and measured lipoprotein and triglycerides. Nuclear magnetic resonance analysis revealed that DHT dose-dependently reduced the cholesterol content of large HDL particles and decreased mean HDL particle size (P < 0.01) and also tended to lower low-density lipoprotein cholesterol without altering other lipoprotein particles. Liver and visceral fat biopsies taken before and after DHT treatment for 1 or 14 d were analyzed by genome-wide microarrays. In liver, DHT did not alter the expression of most genes involved in cholesterol synthesis or uptake but rapidly increased small heterodimer partner (SHP) RNA, along with concomitant repression of CYP7A1, a target of SHP transcriptional repression and the rate-limiting enzyme in bile acid synthesis. DHT regulation of SHP and CYP7A1 also occurs in rats, indicating a conserved mechanism. In adipose tissue, pathway analyses suggested coordinate regulation of adipogenesis, tissue remodeling, and lipid homeostasis. Genes encoding IGF-I and beta-catenin were induced, as were extracellular matrix, cell adhesion, and cytoskeletal components, whereas there was consistent down-regulation of genes involved in triacylglycerol metabolism. Interestingly, cholesterol ester transfer protein RNA was induced rapidly in monkey adipose tissue, whereas its inhibitor apolipoprotein CI was repressed. These data provide insight into the androgenic regulation of lipoprotein homeostasis and suggest that changes in adipose lipoprotein metabolism could contribute to HDL cholesterol reduction.

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