The Endocrine Society
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TAF1 Differentially Enhances Androgen Receptor Transcriptional Activity via Its N-Terminal Kinase and Ubiquitin-Activating and -Conjugating Domains Abstract Aberrant expression of androgen receptor (AR) coregulators has been linked to progression of prostate cancers to castration resistance. Using the repressed transactivator yeast two-hybrid system, we found that TATA binding protein-associated factor 1 (TAF1) interacted with the AR. In tissue microarrays, TAF1 was shown to steadily increase with duration of neoadjuvant androgen withdrawal and with progression to castration resistance. Glutathione S-transferase pulldown assays established that TAF1 bound through its acetylation and ubiquitin-activating/conjugating domains (E1/E2) directly to the AR N terminus. Coimmunoprecipitation and ChIP assays revealed colocalization of TAF1 and AR on the prostate-specific antigen promoter/enhancer in prostate cancer cells. With respect to modulation of AR activity, overexpression of TAF1 enhanced AR activity severalfold, whereas small interfering RNA knockdown of TAF1 significantly decreased AR transactivation. Although full-length TAF1 showed enhancement of both AR and some generic gene transcriptional activity, selective AR coactivator activity by TAF1 was demonstrated in transactivation experiments using cloned N-terminal kinase and E1/E2 functional domains. In keeping with AR coactivation by the ubiquitin-activating and -conjugating domain, TAF1 was found to greatly increase the cellular amount of polyubiquitinated AR. In conclusion, our results indicate that increased TAF1 expression is associated with progression of human prostate cancers to the lethal castration-resistant state. Because TAF1 is a coactivator of AR that binds and enhances AR transcriptional activity, its overexpression could be part of a compensatory mechanism adapted by cancer cells to overcome reduced levels of circulating androgens.
Tập 24 Số 4 - Trang 696-708 - 2010
Bcl-x and Bax Regulate Mouse Primordial Germ Cell Survival and Apoptosis during Embryogenesis
Tập 14 Số 7 - Trang 1038-1052 - 2000
Functional Antagonism of Gonadal Steroids at the 5-Hydroxytryptamine Type 3 Receptor
Tập 12 Số 9 - Trang 1441-1451 - 1998
Closing the Gap: Identification of Human 3-Ketosteroid Reductase, the Last Unknown Enzyme of Mammalian Cholesterol Biosynthesis
Tập 17 Số 9 - Trang 1715-1725 - 2003
Sex-Dependent Liver Gene Expression Is Extensive and Largely Dependent upon Signal Transducer and Activator of Transcription 5b (STAT5b): STAT5b-Dependent Activation of Male Genes and Repression of Female Genes Revealed by Microarray Analysis Abstract Sexual dimorphism in mammalian liver contributes to sex differences in physiology, homeostasis, and steroid and foreign compound metabolism. Many sex-dependent liver genes are regulated by sex differences in pituitary GH secretion, with the transcription factor, signal transducer and activator of transcription (STAT5b), proposed to mediate signaling by the pulsatile, male plasma GH profile. Presently, a large-scale gene expression study was conducted using male and female mice, wild type and Stat5b inactivated, to characterize sex differences in liver gene expression and their dependence on STAT5b. The relative abundance of individual liver RNAs was determined for each sex-genotype combination by competitive hybridization to 23,574-feature oligonucleotide microarrays. Significant sex differences in hepatic expression were seen for 1603 mouse genes. Of 850 genes showing higher expression in males, 767 (90%) were down-regulated in STAT5b-deficient males. Moreover, of 753 genes showing female-predominant expression, 461 (61%) were up-regulated in STAT5b-deficient males. In contrast, approximately 90% of the sex-dependent genes were unaffected by STAT5b deficiency in females. Thus: 1) STAT5b is essential for sex-dependent liver gene expression, a characteristic of approximately 1600 mouse genes (4% of the genome); 2) male-predominant liver gene expression requires STAT5b, or STAT5b-dependent factors, which act in a positive manner; and 3) many female-predominant liver genes are repressed in males in a STAT5b-dependent manner. Several of the STAT5b-dependent male genes encode transcriptional repressors; these may include direct STAT5b targets that repress female-predominant genes in male liver. Several female-predominant repressors are elevated in STAT5b-deficient males; these may contribute to the major loss of male gene expression seen in the absence of STAT5b.
Tập 20 Số 6 - Trang 1333-1351 - 2006
Research Resource: The Androgen Receptor Modulates Expression of Genes with Critical Roles in Muscle Development and Function Abstract
Androgen signaling through the androgen receptor (AR), a ligand-dependent transcription factor within the steroid receptor superfamily, plays an important role in the development and maintenance of many tissues. In muscle, androgens act as anabolic agents that increase both muscle mass and strength; however, a key unanswered question is the mechanism through which AR-mediated gene expression leads to these effects. To gain further insight into the mechanism of AR action in muscle, we identified AR-binding sites in primary human muscle cells using ChIP-on-Chip (chromatin immunoprecipitation coupled with tiling microarray detection of genomic fragments). Through this analysis, we identified 32,518 potential AR-binding sites throughout the genome that were enriched upon androgen treatment. Sequence analysis of these regions indicated that approximately 90% possess a consensus androgen response element or half-site. Among the identified AR-binding sites are genes known to be directly regulated by AR, confirming the validity of our methodology. Additionally, we identified a number of novel AR targets, including genes and micro-RNAs implicated in muscle differentiation and function, suggesting a direct role for AR-mediated transcription in muscle development. Intriguingly, binding sequences for the Mef2 family of transcription factors were enriched in the AR-bound regions, and we show that several Mef2c-dependent genes are direct targets of AR, suggesting a functional interaction between Mef2c and AR in skeletal muscle. Our results provide new insights into the mechanisms by which androgens promote muscle growth and validate AR as a potential therapeutic target for sarcopenia, muscle wasting, and other androgen-related muscle disorders.
Tập 24 Số 8 - Trang 1665-1674 - 2010
Ghrelin Amplifies Dopamine Signaling by Cross Talk Involving Formation of Growth Hormone Secretagogue Receptor/Dopamine Receptor Subtype 1 Heterodimers Abstract
Our objective is to determine the neuromodulatory role of ghrelin in the brain. To identify neurons that express the ghrelin receptor [GH secretagogue receptor (GHS-R)], we generated GHS-R-IRES-tauGFP mice by gene targeting. Neurons expressing the GHS-R exhibit green fluorescence and are clearly evident in the hypothalamus, hippocampus, cortex, and midbrain. Using immunohistochemistry in combination with green fluorescent protein fluorescence, we identified neurons that coexpress the dopamine receptor subtype 1 (D1R) and GHS-R. The potential physiological relevance of coexpression of these two receptors and the direct effect of ghrelin on dopamine signaling was investigated in vitro. Activation of GHS-R by ghrelin amplifies dopamine/D1R-induced cAMP accumulation. Intriguingly, amplification involves a switch in G protein coupling of the GHS-R from Gα11/q to Gαi/o by a mechanism consistent with agonist-dependent formation of GHS-R/D1R heterodimers. Most importantly, these results indicate that ghrelin has the potential to amplify dopamine signaling selectively in neurons that coexpress D1R and GHS-R.
Tập 20 Số 8 - Trang 1772-1785 - 2006
A Short Isoform of the Human Growth Hormone Receptor Functions as a Dominant Negative Inhibitor of the Full-Length Receptor and Generates Large Amounts of Binding Protein
Tập 11 Số 3 - Trang 265-273 - 1997
Inhibition of Ca2+-Independent Phospholipase A2 Results in Insufficient Insulin Secretion and Impaired Glucose Tolerance
Tập 19 Số 2 - Trang 504-515 - 2005
Persistent Parity-Induced Changes in Growth Factors, TGF-β3, and Differentiation in the Rodent Mammary Gland Abstract Epidemiological studies have repeatedly demonstrated that women who undergo an early first full-term pregnancy have a significantly reduced lifetime risk of breast cancer. Similarly, rodents that have previously undergone a full-term pregnancy are highly resistant to carcinogen-induced breast cancer compared with age-matched nulliparous controls. Little progress has been made, however, toward understanding the biological basis of this phenomenon. We have used DNA microarrays to identify a panel of 38 differentially expressed genes that reproducibly distinguishes, in a blinded manner, between the nulliparous and parous states of the mammary gland in multiple strains of mice and rats. We find that parity results in the persistent down-regulation of multiple genes encoding growth factors, such as amphiregulin, pleiotrophin, and IGF-1, as well as the persistent up-regulation of the growth-inhibitory molecule, TGF-β3, and several of its transcriptional targets. Our studies further indicate that parity results in a persistent increase in the differentiated state of the mammary gland as well as lifelong changes in the hematopoietic cell types resident within the gland. These findings define a developmental state of the mammary gland that is refractory to carcinogenesis and suggest novel hypotheses for the mechanisms by which parity may modulate breast cancer risk.
Tập 16 Số 9 - Trang 2034-2051 - 2002