Tag Archives: Linifanib (ABT-869)

Precise coordination from the hypothalamic-pituitary-gonadal axis orchestrates the normal reproductive function.

Precise coordination from the hypothalamic-pituitary-gonadal axis orchestrates the normal reproductive function. HDAC inhibitors downregulate gene expression via Rabbit Polyclonal to Gastrin. repressing Otx2-driven transcriptional activity. This study should provide an insight for our understanding on the effects of HDACs in the reproductive system and suggests that HDACs could be potential novel targets for the therapy of GnRH-related diseases. Introduction Normal reproductive function requires the precise orchestration and integration of sex steroids secretion to effectively coordinate the hypothalamic-pituitary-gonadal axis [1]. As the central regulator gonadotropin-releasing Linifanib (ABT-869) hormone I (GnRH-I) is pulsatily secreted from some highly restricted yet scattered particular nuclei within the hypothalamus and controls the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in pituitary [2] [3]. Dysfunction or hyperfunction of GnRH neurons leads to various pathophysiologic disorders including infertility [4] hypogonadotropic hypogonadism [5] hypothalamic amenorrhea [6] and central precocious puberty [7]. Despite GnRH agonists/analogues and GnRH antagonists are widely applied in clinic these Linifanib (ABT-869) compounds still remain skepticism for some unsolved issues including pharmacokinetic safety and commercial profiles [8]. Therefore elucidation of the exact molecular mechanisms controlling gene expression will improve our understanding on abnormal gonadotropin secretion in various GnRH-related disorders and provide new strategies for treatment of these diseases. Histone deacetylases (HDACs) have gained an increasing attention for their crucial roles in numerous physiological and pathological processes via dynamically regulating gene expression. According to the profiles of global gene expression a range of 2-20% of genes in the genome is affected by HDAC inhibitors (HDACIs) [9]-[11] indicating that a highly restricted set of cellular genes is sensitive to changes in histone acetylation [12]. Recently emerging evidence indicates the involvement of HDACs in maintaining normal reproductive function. HDACs participate in spermatogenesis [13] mediate and gene repression in immature gonadotropes [14] [15] and inhibit androgen receptor transcriptional activity [16]. However the exact roles of HDACs in the modulation of neuronal function of GnRH neurons have remained unclear and need to be further delineated. So far at least 18 HDACs have been identified in mammals in which they are divided into four classes based on their structure and functions. Linifanib (ABT-869) Both Class I (HDACs 1-3 and 8) and class II (HDACs 4-7 Linifanib (ABT-869) and 9-10) HDACs are Zn-dependent enzymes which usually combine with other proteins to form a large multi-protein complex that increases the stringency of HDACs recruitment to a particular locus in chromatin to deacetylate histones [14] [17] [18]. In the present study we initially observed that genes were co-expressed in the mouse immortalized GnRH neuronal cells GT1-7 which are representative of mature postmigratory GnRH neurons. Two HDAC inhibitors (HDACIs) trichostatin A (TSA) and valproic acid (VPA) induced marked inhibition of gene transcription and the suppression was connected with a specific region of gene promoter which contains two consensus Otx2 binding sites. Otx2 a vertebrate homologue of orthodenticle has been demonstrated to activate basal and Linifanib (ABT-869) also enhancer-driven transcription of gene in several vertebrate Linifanib (ABT-869) species [19] [20]. We hypothesized that Otx2 may be involved in the HDACIs-induced attenuation of transcription. The analysis of transcript and protein levels showed that expression was..