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Severe male factor infertility: Genetic consequences and recommendations for genetic testing
Published in David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham, Textbook of Assisted Reproductive Techniques, 2017
Katrien Stouffs, Willy Lissens, Sara Seneca
Kennedy’s disease or spinal and bulbar muscular atrophy is a neuromuscular disease causing muscular weakness that is associated with testicular atrophy and leads to oligozoo- spermia or azoospermia. It is an X-linked disease caused by an expanded (CAG) trinucleotide repeat in the transactivation domain of the androgen receptor gene (61, 62). If treated with ICSI, genetic counseling is again indicated. However, point mutations in the androgen receptor gene might result in androgen insensitivity through impaired binding of dihydrotestosterone to the receptor, which will interfere with sexual development. The resulting syndrome is testicular feminization or androgen insensitivity syndrome, causing a (partial) female phenotype (63, 64). The presenting problem here will not (only) be male infertility. Patients with an autosomal recessive 5a-reductase deficiency and therefore unable to synthesize dihydrotestosterone from testosterone may theoretically present at the clinic with azoospermia and pseudohermaphroditism (65, 66).
Epstein–Barr Virus and Treatment of Its Infection
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Tarun Jha, Amit Kumar Halder, Nilanjan Adhikari
Immediate early gene products are considered important because these are responsible for the translation from latent to lytic phase (Kieff and Rickinson 2007). These gene products also transactivate E and L gene products. The best known IE gene product is BZLF1 or Zebra. It serves as a checkpoint for initiation of the replicative cycle. BZLF1 is a DNA-binding transactivator protein involved in triggering expression of the lytic genes and downregulation of latent genes. These lead to cell death and release of infectious virions. BZLF1 protein consists of three domains: (a) one transactivation domain, (b) a basic domain with high homology to a conserved region of the c-junc/c-fos family of transcription factor, and (c) a p53-interacting domain. Overexpression of p53 protein as well as gamma irradiation induces the expression of Zebra leading to initiation of lytic cycle. The Zebra expression was also found in some EBV-associated tumor cells (Middeldorp et al. 2003). It also helps in escaping immune response by interfering with interferon γ (IFNγ) signaling. The Zebra protein reduces the expression of IFNγ and thus results in inhibition of IFNγ-induced STAT1 tyrosine phosphorylation and subsequent disruption of MHC-II upregulation (Morrison et al. 2001). Other known IE products are BRLF1, BRRF1, and BI’LF4 transactivator genes. Transcription of IE genes occurs even in the presence of protein synthesis inhibitors.
Molecular and Biochemical Approaches to the Etiology of Prostate Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
The N-terminal transactivation domain of AR is encoded by one large exon that contains two highly polymorphic trinucleotide repeats, coding, respectively, for glutamine (CAG) and glycine (GGN, where N is any one of the four nucleotides). A more than twofold expansion in the number of glu-tamine repeats causes Kennedy’s disease, an androgen insensitivity syndrome (29), possibly through defective binding to an AR coactivator (30). Relatively long CAG repeats are also associated with infertility in otherwise healthy men (31) and have been related to decreased levels of T, free T, and albumin-bound T (32) and to decreased transcriptional activation by AR (33).
E2F1 as a molecular drug target in ovarian cancer
Published in Expert Opinion on Therapeutic Targets, 2019
Rossella Farra, Barbara Dapas, Mario Grassi, Fabio Benedetti, Gabriele Grassi
E2F1 belongs to the transcription factor family named E2Fs, characterized by activating (E2F1––E2F3a), repressing (E2F3b––E2F5) or inhibiting (E2F6––E2F8) activities on the transcription of many genes including cell cycle genes [4]. E2F1 (Figure 1(a)) contains a DNA binding domain (DBD) a transactivation domain (TD) and a dimerization domain (DD). DBD allows the binding to gene promoter thus inducing transcription. DD is necessary to bind the dimerization partner (DP) which allows DNA binding. Finally, via TD, E2F1 interacts with its inhibitor retinoblastoma protein (pRB) which binds to E2F1-DP in resting cells. In the presence of proliferation stimuli, pRb is phosphorylated by cyclin D/cdk4-6 (cyclin dependent kinase) kinase and thus released from the complex E2F1/DP (Figure 1(b)). Once detached from pRb, E2F1/DP triggers the transcription of different genes including cyclin E1 that in turn, bound to its cdk2, phosphorylates pRb further allowing E2F1-DP release and activation. Not only E2F1/DP promotes cell growth, it can also activate apoptosis via p53-dependent and p53-independent mechanisms, thus highlighting its double biological role.
Abemaciclib for the treatment of HR+/HER2- breast cancer
Published in Expert Review of Precision Medicine and Drug Development, 2018
The direct interaction of RB with cell cycle promoter proteins is responsible for transcriptional repression and consequent cessation of cell division. The family of E2F transcriptional regulatory proteins has a transactivation domain and can activate the expression of target genes when binding to DNA leading to the progression of the G1 to S phase. The binding of RB to these E2F complexes, mainly E2F1, antagonizes the transcription of essential genes for cell replication, converting the E2F1 binding activity to a potent repressor element on specific proliferation genes [16]. Conversely, in favorable conditions for cellular growth, cyclin D accumulation drives the formation of active heterodimers CDK4 and CDK6 that phosphorylate RB and destabilize the RB–E2F1 complex, thereby allowing E2F1-dependent transcription to resume [17]. The CDK4/6 amplified pathway is described in several tumor types (breast, soft tissue sarcoma, glioblastoma, and melanoma) as an important tumor-surviving mechanism [17].
Tri-nucleotide consortium of androgen receptor is associated with low serum FSH and testosterone in asthenospermic men
Published in Systems Biology in Reproductive Medicine, 2018
Haroon Latif Khan, Shahzad Bhatti, Sana Abbas, Yousaf Latif Khan, Muhammad Aslamkhan, Rosa Maria Marquez Gonzalez, Gerardo Rodriguez Gonzalez, Hikmet Hakan Aydin, Magali Segundo Trinidad
One of the important role of the AR receptor is to maintain the integrity of male phenotype and spermatogenesis through T regulation [Levin and Hammes 2016]. A key component resides between amino acid residues141 and 338, the transactivation domain (TAD). This is highly polymorphic and inherent variations therein may affect androgen receptor mediated gene regulation of androgen receptor responsive elements/genes. The extent of variation of AR size is in part because polymorphic trinucleotide repeats reside in the TAD within the first exon.