Pax6 Represses Androgen Receptor-Mediated Transactivation by Inhibiting Recruitment of the Coactivator SPBP

The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer

HOXC8 Inhibits Androgen Receptor Signaling in Human Prostate Cancer Cells by Inhibiting SRC-3 Recruitment to Direct Androgen Target Genes

Abstract HOX (homeobox) genes encode homeodomain-containing transcription factors critical to development, differentiation, and homeostasis. Their dysregulation has been implicated in a variety of cancers. Previously, we showed that a subset of genes of the HOXC cluster is upregulated in primary prostate tumors, lymph node metastases, and malignant prostate cell lines. In the present study, we show that HOXC8 inhibits androgen receptor (AR)-mediated gene induction in LNCaP prostate cancer cells and HPr-1 AR, a nontumorigenic prostate epithelial cell line. Mechanistically, HOXC8 blocks the AR-dependent recruitment of the steroid receptor coactivators steroid receptor coactivator-3 (SRC-3), and CREB binding protein to the androgen-regulated prostate-specific antigen gene enhancer and inhibits histone acetylation of androgen-regulated genes. Inhibition of androgen induction by HOXC8 is reversed upon expression of SRC-3, a member of the SRC/p160 steroid receptor cofactor family. Coimmunoprecipitation studies show that HOXC8 expression inhibits the hormone-dependent interaction of AR and SRC-3. Finally, HOXC8 expression increases invasion in HPr-1 AR nontumorigenic cells. These data suggest a complex role for HOXC8 in prostate cancer, promoting invasiveness while inhibiting AR-mediated gene induction at androgen response element–regulated genes associated with differentiated function of the prostate. A greater understanding of HOXC8 actions in the prostate and its interactions with androgen signaling pathways may elucidate mechanisms driving the onset and progression of prostate cancer. Mol Cancer Res; 8(12); 1643–55. ©2010 AACR.</jats:p

PV &apos;04 REVIEW Masterpage

ABSTRACT: Hydrocephalus is a common congenital or acquired neurologic disorder in dogs and cats. Although a differential diagnosis for the disorder exists, the underlying cause of congenital hydrocephalus is often unknown. Medical treatment decreases cerebrospinal fluid volume and production but offers only temporary palliation of clinical signs. Advances in shunt technology have allowed ventriculoperitoneal shunt placement to treat congenital hydrocephalus and as an adjunct in managing secondary hydrocephalus.This article discusses the pathophysiology and medical and surgical treatment of hydrocephalus. Article #

A Prospective Evaluation of CT in Acutely Paraparetic Chondrodystrophic Dogs

The clinical usefulness of computed tomography (CT) as a sole diagnostic modality in identifying disc lesion(s) in chondrodystrophic breeds presenting with acute signs of intervertebral disc disease (IVDD) is incompletely characterized. CT was used prospectively to determine the validity of this tool. Neurologic examinations and CT scans were performed on all dogs at presentation. Surgical decompression was based on those findings. Clinical follow-up examinations were performed on days 1 and 14 postsurgically. CT detected a lesion consistent with clinical findings in 63 of 69 cases (91%). All 63 dogs with Hansen type I IVDD lesions were identified on CT alone. The surgeon and radiologist agreed on lesion level in 72 of 78 lesions (92%) and lateralization in 71 of 78 lesions (91%). Improvement in neurologic grade was documented in 60 of 69 dogs (87%) by 14 days. CT imaging can be used as a single imaging modality in chondrodystrophic dogs presenting with acute paresis. CT used in this manner is a reliable and noninvasive tool for detecting spinal compression secondary to IVDD in chondrodystrophic dogs.</jats:p