Progesterone receptor (PR), a ligand-activated transcription factor, is a key regulator of cellular proliferation and differentiation in reproductive tissues. The transcriptional activity of PR is influenced by co-regulatory proteins typically expressed in a tissue-and cellspecific fashion. We previously demonstrated that basic transcription element-binding protein-1 (BTEB1), a member of the Sp/Krü ppel-like family of transcription factors, functionally interacts with the two PR isoforms, PR-A and PR-B, to mediate progestin sensitivity of target genes in endometrial epithelial cells in vitro. Here we report that ablation of the Bteb1 gene in female mice results in uterine hypoplasia, reduced litter size, and increased incidence of neonatal deaths in offspring. The reduced litter size is solely a maternal genotype effect and results from fewer numbers of implantation sites, rather than defects in ovulation. In the early pregnant uterus, Bteb1 expression in stromal cells temporally coincides with PR-A isoform-dependent decidual formation at the time of implantation. Expression of two implantation-specific genes, Hoxa10 and cyclin D3, was decreased in uteri of early pregnant Bteb1-null mutants, whereas that of Bteb3, a related family member, was increased, the latter possibly compensating for the loss of Bteb1. Progesterone responsiveness of several uterine genes was altered with Bteb1-null mutation. These results identify Bteb1 as a functionally relevant PR-interacting protein and suggest its selective modulation of cellular processes that are regulated by PR-A in the uterine stroma.

Chronic and excessive alcohol consumption is an important and modifiable risk factor for type 2 diabetes. We previously reported elevations in hepatic Class 1 alcohol dehydrogenase (ADH) expression in ethanol-fed rats correspondent with reduced levels of mature, nuclear sterol-regulatory element-binding protein-1 (SREBP-1), an insulin-induced transcriptional repressor of the ADH gene. In this report, we have studied the effects of insulin and ethanol on ADH gene expression in a highly differentiated rat hepatoma cell line (FGC-4), as well as the in vivo effects of chronic intake of an ethanol-containing diet on hepatic insulin signaling. Insulin inhibited ADH gene expression, and this was abolished by LY294002 (a phosphatidylinositol 3-kinase inhibitor) and small interfering RNA knockdown of SREBP-1. Chronic ethanol intake led to decreased phosphorylation of Akt (protein kinase B) at Writings from as early as the 17th century, as well as modern epidemiological studies, suggest that chronic and excessive alcohol consumption is positively associated with the onset of type 2 diabetes (1-5). Ethanol intake has been reported to decrease glucose uptake and utilization consistent with the development of insulin resistance, a central component of diabetes (6). Results from these previous studies suggest that the ethanol impairment of insulin action is likely to be downstream from PI3 2 kinase; however, the molecular mechanisms underlying the effects of alcohol on insulin resistance and type-2 diabetes remain to be determined (7).We previously reported that chronic intragastric infusion of an ethanol-containing diet to rats results in unique and predictably recurring cyclic fluctuations in plasma ethanol concentrations (8) as a consequence of cyclic expression of the major alcohol metabolizing enzyme, hepatic Class 1 alcohol dehydrogenase (ADH). Further studies from our laboratory demonstrated that alcohol induces hepatic ADH gene transcription via decreased levels of nuclear SREBP-1c protein, a negative regulator of the ADH gene (9). SREBP-1c is encoded by an insulinresponsive gene (10) and is an important early mediator in the pathway of insulin action in the liver (11). These observations led to the current hypothesis under study, namely that ethanol may suppress nuclear SREBP-1c via disruption of insulin signaling, which may be a potential link between alcohol consumption and insulin resistance. In this study, we elucidate the mechanism by which chronic ethanol intake inhibits insulin action and identify TRB3, a previously identified modulator of Akt signaling, as a primary ethanol-responsive modifier of insulin signaling (12). EXPERIMENTAL PROCEDURESMaterials-All chemicals, unless otherwise specified, were purchased from Sigma. Antibodies were purchased from commercial suppliers: SREBP-1 was from Santa Cruz Biotechnology Inc. (Santa Cruz, CA); GSK3, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) were from Upstate Biotechnology (Lake Placid, NY); phospho-GSK3, Akt, phospho-Akt 473 , phospho-Akt 30...

Loss of KLF9 coregulation of endometrial stromal PGR-responsive gene networks may underlie progesterone resistance in endometriosis.