Human BHMT blocking peptide

LH activation of the epidermal growth factor receptor/RAS/ERK1/2 pathway is essential for ovulation and luteinization because granulosa cell (GC) depletion of Erk1/2 (Erk1/2(gc-/-) mice) renders mice infertile. As mediators of ERK1/2-dependent GC differentiation, the CCAAT/enhancer-binding proteins, (C/EBP)alpha and C/EBP beta, were also disrupted. Female Cebpb(gc-/-) mutant mice, but not Cebpa(gc-/-) mice, were subfertile whereas Cebpa/b(gc-/-) double-mutant females were sterile. Follicles failed to ovulate, ovaries were devoid of corpora lutea, luteal cell marker genes (Lhcgr, Prlr, Ptgfr, Cyp11a1, and Star) were absent, and serum progesterone levels were low. Microarray analyses identified numerous C/EBP alpha/beta target genes in equine chorionic gonadotropin (eCG)-human (h)CG-treated mice. At 4 h post-hCG, a subset (19%) of genes altered in the Cebpalb-depleted cells was also altered in Erk1/2-depleted cells; hence they are common effectors of ERK1/2. Additional genes down-regulated in the Cebpalb-depleted cells at 8 and 24 h post-hCG include known (Akr1b7, Runx2, Star, Saa3) and novel (Abcb1b, Apln, Igfbp4, Prlr, Ptgfr Timp4) C/EBP targets and effectors of luteal and vascular cell development. Bhmt, a gene controlling methionine metabolism and thought to be expressed exclusively in liver and kidney, was high in wild-type luteal cells but totally absent in Cebpalb mutant cells. Because numerous genes potentially associated with vascular development were suppressed in the mutant cells, C/EBP alpha/beta appear to dictate the luteinization process by also controlling genes that regulate the formation of the extensive vascular network required to sustain luteal cells. Thus, C/EBP alpha/beta mediate the terminal differentiation of GCs during the complex process of luteinization. (Molecular Endocrinology 25: 253-268, 2011)

Both thyroid hormone ( T 3) and growth hormone (GH) are important regulators of somatic growth in birds and mammals. Although T-3-mediated gene transcription is well known, the molecular basis of T 3 interaction with GH on growth and development of birds remains unknown. In earlier studies, we discovered that exogenous GH alone increased accumulation of visceral fat in young chickens, while the combination of GH injections and dietary T 3 worked synergistically to deplete body fat. In the present study, cDNA microarray and quantitative RT-PCR analyses enabled us to examine hepatic gene expression in young chickens after chronic manipulation of thyroid status and GH injection alone or in combination with T-3. Thyroid status modulates expression of common and unique sets of genes involved in a wide range of molecular functions (i.e., energy metabolism, storage and transport, signal transduction, protein turnover and drug detoxification). Hepatic expression of 35 genes was altered by hypothyroidism ( e. g., ADFP, ANGPTL3, GSTA, CAT, PPARG, HMGCL, GHR, IGF1, STAT3, THRSP alpha), whereas hyperthyroidism affected expression of another cluster of 13 genes ( e. g., IGFBP1, KHK, LDHB, BAIA2L1, SULT1B, TRIAD3). Several genes were identified which have not been previously ascribed as T 3 responsive ( e. g., DEFB9, EPS8L2, ARHGAP1, LASS2, INHBC). Exogenous GH altered expression of 17 genes ( e. g., CCAR1, CYP2C45, GYS2, ENOB, HK1, FABP1, SQLE, SOCS2, UPG2). The T-3+GH treatment depleted the greatest amount of body fat, where 34 differentially expressed genes were unique to this group ( e. g., C/EBP, CDC42EP1, SYDE2, PCK2, PIK4CA, TH1L, GPT2, BHMT). The marked reduction in body fat brought about by the T-3+GH synergism could involve modulation of hormone signaling via altered activity of the Ras superfamily of molecular switches, which control diverse biological processes. In conclusion, this study provides the first global analysis of endocrine ( T 3 and GH) regulation of hepatic gene transcription in the chicken. Copyright (c) 2007 S. Karger AG, Basel