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Telomerase and cancer
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
Unlike androgen, the upregulation of hTERT upon estrogen exposure appears to involve a direct effect on its promoter. Indeed, the hTERT promoter contains a hormone response element37 that interacts specifically with the activated estrogen receptor42. Accordingly, estrogen has been shown to upregulate hTERT in the MCF-7 breast cancer cell line43 and ovary epithelial cells42. Since progesterone generally opposes the action of estrogens in reproductive tissues, a recent study investigated its possible role in telomerase activation44. Curiously, progesterone administration to breast and endometrial cancer cell lines led to a transient increase in hTERT expression, which peaked after 12 h and then decreased. In the presence of estrogen, progesterone had a synergistic effect on hTERT expression for 24 h, but antagonized the effect of estrogen over a longer period of time, and was found to result in diminished hTERT expression.
Thyroid disorders, dementia and Down syndrome
Published in Vee P. Prasher, Down Syndrome and Alzheimer’s Disease, 2018
Thyroid dysfunction is known to influence zinc metabolism, and zinc status in the body is known to influence thyroid function, although the reasons for these effects are not well understood. Zinc may mediate the binding of thyroid hormone receptor to the thyroid hormone response element via its ‘zinc fingers.’84,90 (Zinc fingers are small protein domains in which zinc plays a structural role contributing to the stability of the domains.) Zinc is also a cofactor of cytoplasmic Cu,Zn-superoxide dismutase-1 (SOD1), the enzyme that dismutates superoxide radicals into peroxide in cells99 (for further information on SOD1 and its possible role in AD in DS, seeChapter 5).
Protein Function As Cell Surface And Nuclear Receptor In Human Diseases
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Urmila Jarouliya, Raj K. Keservani
Nuclear receptors (NRs) are proteins that share considerable amino acid sequence similarity in two highly conserved domains – the DNA binding (DBD) and the ligand binding domains (LBD). These domains are responsible for binding specific DNA sequences and small lipophilic ligands [96]. NRs Comprises a large, ancient, superfamily of eukaryotic transcription factors that govern a wide range of metabolic, homeostatic, and developmental pathways, and which have been implicated in disease states including cancer, inflammation, and diabetes. The ability of NRs to activate or repress gene transcription is modulated through direct binding of small lipophilic ligands which induce conformational changes in their related receptor. These changes are structural in nature and lead to the recruitment of coactivator or corepressor complexes, ultimately regulating the expression of target genes to whose response elements NRs are bound (Figure 1.3). AF-1: Activation factor 1, it is a ligand-independent factor and responsible for gene activationDBD: DNA binding domain is composed of two highly conserved zinc fingers and responsible for targeting the receptor to highly specific DNA sequences comprising a hormone response element (RE), it also includes the hinge region.LBD: Ligand binding domain, capable of binding to small lipophilic molecules such as steroids, retinoids, and vitamins which regulate the activity of these receptors.AF-2: Activation factor 2, it is a legend dependent and responsible for the gene activation function.
Bilateral cranial nerve 6 palsy in a patient with multiple sclerosis and vitamin D-dependent rickets
Published in Neuro-Ophthalmology, 2022
Aishwarya Sriram, Devon Joiner, Kevin Hsu, Cheng Zhang
Type 2A, commonly known as vitamin D-resistant rickets, is due to a defect in the vitamin D receptor gene, thus causing resistance to 1,25-dihydroxyvitamin D (vitamin D 1,25-[OH]). It is similarly autosomal recessive; however, these patients tend to have severe, early-onset rickets, and supplementation may not improve the condition, particularly in patients with nonsense mutations in the DNA-binding domain. Type 2B, whose inheritance pattern is unknown, is clinically similar to type 2A but is due to abnormal expression of a hormone response element-binding protein, which interferes with the vitamin D receptor function. In these patients, there are low levels of 25-hydroxyvitamin D (vitamin D 25-OH) with compensatory elevated levels of vitamin D 1,25(OH). Types 2A and 2B can only be distinguished by genetic testing.5,6
Regulation of the apolipoprotein M signaling pathway: a review
Published in Journal of Receptors and Signal Transduction, 2022
HNF-4α is an upstream regulator of HNF-1α. Mutations in the human HNF-4α gene cause an autosomal dominant disease, MODY1. HNF-4α binds to the −33/-21 region of the hormone response element in the proximal apoM promoter and positively regulates the expression of apoM [45]. Ding et al. [27] demonstrated that, compared with the liver tissue of young mice, the expression level of regulatory factor HNF-4α in liver tissue of old mice was significantly inhibited and the synthesis of apoM was reduced, resulting in attenuated S1P signaling. Furthermore, they demonstrated that the suppression of HNF-4α expression was associated with reduced sirtuin-1 level in the livers of aged mice. In summary, activation of the sirtuin-1/HNF-4α/apoM/S1PR1 pathway promoted regeneration and anti-fibrosis in injured lungs and kidneys. Targeting the apoM signaling pathway in the liver to promote regeneration of distant organs is therefore a potential therapy for age-related fibrosis.
Penetrance of MYOC gene mutation in primary open-angle glaucoma: A systematic review and meta-analysis
Published in Ophthalmic Genetics, 2022
Juan-Juan Xie, Guo-Wei Zhang, Hai-Yue Cui, Na Li, Xing-Xing Liu, Meng-Yao Hao, Shao-Wen Wang, Hong Lu
MYOC gene located in GLC1A locus is the earliest and most common POAG pathogenic gene, which was first identified by Stone et al. in 1997 (10). More than 100 MYOC gene mutations (about 85% of which are missense) have been reported in association with POAG up to now (11). Including three exons and two introns, the total length of MYOC gene is about 20 kb (the length of the three exon coding regions was 604 bp, 126 bp, and 785 bp, respectively). There are two main homologous domains: the N-terminal myosin domain (containing a protein-bound leucine zipped domain and a myosin-like domain) and the C-terminal olfactomedin domain. MYOC gene encodes a glycoprotein consisting of 504 amino acids with a relative molecular weight of approximately 55 kDa and is glycosylated at amino acid residues at 57–59. MYOC gene has a promoter region of approximately 5 kb, which contains glucocorticoid binding site, thyroid hormone response element (TRE), and activator protein L(AP1) in this region. Ninety percent of MYOC mutations were mainly concentrated in the olfactomedin homologous region of exon 3, and few mutations are located in exon 1 and exon 2 (12). MYOC gene is expressed not only in eye tissues, such as cornea, sclera, trabecular reticulum, iris, ciliary body, retina and optic nerve papilla, but also in stomach, skeletal muscle, thyroid, and other parts of the body; the concentration varies greatly in various tissues (the concentration is higher in trabecular and ciliary body) (13).