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Regulation of the Pituitary Gland by Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The effects of GCs on the HPA axis is exerted at different sites and by various mechanisms. One integrative site is the hippocampus, which contains the highest concentration of glucocorticoid receptors in the CNS. Another site is the PVN, where the GCs inhibit the synthesis and release of both CRH and AVP. At the pituitary corticotrophs, GCs inhibit the transcription of POMC and antagonize CRH-stimulated ACTH release. They also repress cell cycle regulators such as L-Myc, N-Myc and E2F2 and suppress corticotroph proliferation.
Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
Stress factors can induce upregulated miRNA expression [85]. Permanent growth arrest, seen either in replicative senescence via serial passaging or in premature senescence induced by peroxide treatment, is associated with significant upregulated expression of miRNAs. This stress-induced activation of miRNAs may promote tissue aging. Certain miRNAs, including miR-210 and miR-373, dampen the expression of key DNA repair proteins [87]. Interestingly, in a screen of over 800 miRNAs in human peripheral blood mononuclear cells, 16.5% of the miRNAs declined in abundance with age, while only 2.5% increased [88]. It has been shown that miR-24, significantly downregulated with age, can target E2F2, p16INK4a, MKK4, and H2AX mRNAs. Several miRNAs downregulated with age are known to be associated with cancers (miR-103, -107, -128, -155, and -221). These findings underscore the importance of miRNA expression in age-related diseases, such as cancer. PI3K (phosphatidylinositol-3-kinase) is a known integrator of multiple signaling pathways that promote tumorigenesis. Downregulation of miR-221 with age leads to increased PI3K mRNA and protein. Thus, miR-221 may be a modulator of pathways important in aging and tumorigenesis.
Genetics of neuroblastoma
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
John M. Maris, Garrett M. Brodeur
Several genes have been analyzed as possible candidates for the 1p36 neuroblastoma suppressor gene. These include the TP53 homolog TP73 (Kaghad et al., 1997) the CDK2 homolog CDC2L1 (p58); (Lahti et al., 1994) the transcription factors HKR3 (Maris et al., 1996b), DAN (Shapiro et al., 1993), PAX7 (Enomoto et al., 1994), ID3 (Deed et al., 1994) and E2F2 (Saito et al., 1995); the transcription elongation factor TCEB3 (Elongin A) (Aso et al., 1995); and two members of the tumor necrosis factor receptor family, TNFR2 (Bettinger et al., 1996) and DR3 (Marsters et al., 1996). However, each of these genes except DR3 and HKR3 are located outside the current consensus region, and no mutations have been found in the non-deleted allele of any candidate (White et al., 1997). Thus, none of these candidates function as a classic tumor suppressor for neuroblastoma, but the possibility that haploinsufficiency for any candidate gene results in enhanced tumorigenicity has not been ruled out.
Novel approaches to targeted protein degradation technologies in drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Yu Xue, Andrew A. Bolinger, Jia Zhou
Based on proteome microarray screening, Tu’s group reported bufalin (30), the main active ingredient of some Chinese medicine, could significantly promote TF E2 factor 2 (E2F2) degradation through an atypical E3 ligase ZFP91-mediated pathway [45]. Abnormal E2F2 expression was highly correlated with poor prognosis in various cancers. However, E2F2 was considered ‘undruggable’ because it lacks a typical ligand-binding domain. In this study, 30 acted as an MG bound to ZFP91 and exhibited a specific binding capacity with E2F2 itself. Structurally, 30 was comprised of androsterone, which was responsible for E2F2 binding, and α-pyrone, which covalently interacted with the Cys349 of ZFP91 through electrophilic addition. This study suggests that as a novel atypical E3 ligase, ZFP91 may potentially induce degradation of various neosubstrates other than E2F2. The pyrone group on bufalin may also provide a general structural moiety for discovering novel covalent MGs.
The role of the Fas/FasL signaling pathway in environmental toxicant-induced testicular cell apoptosis: An update
Published in Systems Biology in Reproductive Medicine, 2018
In mammalian spermatogenesis, sperm output depends on the coordination of proliferation, differentiation, and gradual maturation of the various types of germ cells (Xu et al. 2016). E2F2-induced germ cell apoptosis is particularly evident in the first wave of spermatogenesis (Rotgers et al. 2015), while the Fas/FasL system mainly regulates the first wave of spermatogenesis and mediates germ cell apoptosis induced by MEHP (Lin et al. 2010). Moreover, caspase-3, −8, and −9 are active in germ cell apoptosis during the first wave of rat spermatogenesis, and Fas/FasL signaling pathway may therefore play an important role in germ cell apoptosis during puberty in the rat (Moreno et al. 2006). In the reproductive system, Fas is the TNF/NGFR superfamily type I transmembrane protein receptor expressed on the surface of germ cells (Li et al. 2006). Apoptosis is initiated when the intracellular death domain of Fas reacts with FasL receptors on Sertoli cells (Yao et al. 2009).