Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concept of classical endocrine control of ovarian function has now been extended to a more complex regulator system, including paracrine and autocrine modulating mechanisms. Among many factors, locally produced intraovarian insulin-like growth factors (IGFs) and the binding proteins (IGFBPs) and renin-angiotensin system (RAS) have been shown to play an important role in the control of folliculogenesis and ovulation. Growth hormone (GH) amplified gonadotropin actions in the process of follicular development and ovulation, at least in part, stimulating ovarian IGF-I production. IGF-I as well as IGFBPs were produced by ovarian granulosa cells. IGF-I acted synergistically with gonadotropins in the stimulation of a variety of granulosa cell functions, including estradiol (E2) and progesterone production and plasminogen activator (PA) activity. Furthermore, rabbit ovarian cells and rat granulosa cells possessed specific IGF type I receptors. The biological effects of IGF-I, including intrafollicular PA activities and ovarian steroidogenesis, were modulated by a family of IGFBPs in a complex manner. In the ovary IGFBP-3 appeared to neutralize the actions of gonadotropin and IGF-I, probably via its ability to sequester IGF-I, in the process of follicular growth, oocyte maturation, and ovulation. A functional local RAS is also known to exist in the ovary. Angiotensin II (Ang II) at 2-h intervals induced oocyte maturation, ovulation, and the production of E2 and prostaglandins (PGs) in the in vitro perfused rabbit ovaries in the absence of gonadotropin. In addition, the intrafollicular Ang II content and renin-like activity were enhanced during the ovulatory process by exposure to hCG, and the concomitant addition of saralasin inhibited hCG-induced ovulation in a dose-dependent manner. Captopril, an inhibitor of angiotensin converting enzyme, significantly inhibited the resumption of meiosis in the ovulated ova and follicular oocytes stimulated by hCG. Autoradiographic study revealed that AT2 receptors were predominantly located in granulosa cells, whereas AT1 receptors were more concentrated in the stroma and the thecal layers. Ang II-stimulated production of E2 and PGs and ovulation were significantly blocked by PD123319, a selective nonpeptide antagonist for AT2 receptors. The increase in ovarian IGF-I synthesis by exposure to hCG or GH induced the stimulation of intrafollicular PA activities. IGFBP-3 blocked the stimulatory effects of gonadotropin in the ovulatory process by neutralizing endogenously produced IGF-I, resulting in reduced intrafollicular PA activities. The increase in intrafollicular PA activities significantly stimulated the generation of Ang II in the preovulatory follicles by an activation of prorenin to renin and/or by the direct cleavage of angiotensinogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Regulatory system and physiological significance of local factors in the ovary during follicular development and maturation]. 759 85

Serum levels of insulin and insulin-like growth factors and their binding proteins (IGFs and IGFBPs, respectively) are changed in human neurodegenerative diseases of very different etiology, such as Alzheimer's disease, amyotrophic lateral sclerosis, or cerebellar ataxia. However, the significance of these endocrine disturbances is not clear. We now report that in two very different inherited neurodegenerative conditions, ataxia-telangiectasia (AT) and Charcot-Marie-Tooth 1A (CMT-1A) disease, serum levels of IGFs are also altered. Both types of patients have increased serum IGF-I and IGFBP-2 levels, and decreased serum IGFBP-1 levels, while only AT patients have high serum insulin levels. Furthermore, serum IGFs are also changed in three different animal models of neurodegeneration: neurotoxin-induced motor discoordination, diabetic neuropathy, and hereditary cerebellar ataxia. In these three models, serum insulin levels are significantly decreased, serum IGF-I and IGFBP-1, -2, and -3 are decreased in diabetic and neurotoxin-injected rats, while serum IGFBP-1 is increased in hereditary ataxic rats. Altogether, these observations indicate that a great variety of neurodegenerative diseases show endocrine perturbations, resulting in changes in serum IGFs levels. These perturbations are disease-specific and are probably due to metabolic and endocrine derangements, nerve cell death, and sickness-related disturbances associated to the neurodegenerative process. Our observations strongly support the need to evaluate serum IGFs in other neurodegenerative conditions.
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PMID:Neurodegeneration is associated to changes in serum insulin-like growth factors. 1111 63

The ATM gene is mutated in the syndrome of ataxia telangiectasia (AT), associated with neurologic dysfunction, growth abnormalities, and extreme radiosensitivity. Insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor with tyrosine kinase activity that can mediate mitogenesis, cell transformation, and inhibition of apoptosis. We report here that AT cells express low levels of IGF-IR and show decreased IGF-IR promoter activity compared with wild-type cells. Complementation of AT cells with the ATM cDNA results in increased IGF-IR promoter activity and elevated IGF-IR levels, whereas expression in wild-type cells of a dominant negative fragment of ATM specifically reduces IGF-IR expression, results consistent with a role for ATM in regulating IGF-IR expression at the level of transcription. When expression of IGF-IR cDNA is forced in AT cells via a heterologous viral promoter, near normal radioresistance is conferred on the cells. Conversely, in ATM cells complemented with the ATM cDNA, specific inhibition of the IGF-IR pathway prevents correction of the radiosensitivity. Taken together, these results establish a fundamental link between ATM function and IGF-IR expression and suggest that reduced expression of IGF-IR contributes to the radiosensitivity of AT cells. In addition, because IGF-I plays a major role in human growth and metabolism and serves as a survival and differentiation factor for developing neuronal tissue, these results may provide a basis for understanding other aspects of the AT syndrome, including the growth abnormalities, insulin resistance, and neurodegeneration.
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PMID:ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response. 1117 10

Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder sharing a pleiotropic phenotype with ataxia-telangiectasia (A-T), including increased radiosensitivity and cancer disposition. Insulin-like growth factor I receptor (IGF-IR) expression is reportedly decreased in A-T cells, which is thought to contribute to its increased radiosensitivity. In this study, we investigated whether the same mechanism underlies the radiosensitivity of NBS cells. GM7166VA7 cells lacking NBS1 protein displayed a phenotype of increased radiosensitivity, while the introduction of NBS1 cDNA conferred radioresistance comparable to normal cells. IGF-IR expression levels were essentially the same among normal, NBS, and NBS1-complemented NBS cells. There was no significant difference between NBS and NBS1-complemented cells in activation of major downstream pathways of IGF-IR upon IGF-I stimulation, including phosphatidylinositol-3(') kinase (PI3-K) and mitogen-activated protein kinase (MAPK). Collectively, IGF-IR-related events are unlikely to be disrupted in NBS cells, and therefore, defects in IGF-IR signaling do not explain the increased radiosensitivity of NBS cells.
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PMID:Insulin-like growth factor I receptor is expressed at normal levels in Nijmegen breakage syndrome cells. 1214 27

We examined the possibility of whether angiotensin (Ang) II type 1 (AT1) and type 2 (AT2) receptor stimulation differentially regulates collagen production in mouse skin fibroblasts. Both AT1 and AT2 receptors were expressed in neonatal skin fibroblasts prepared from wild-type mice to a similar degree, and the AT1a receptor was exclusively expressed as opposed to the AT1b receptor. In wild-type fibroblasts, Ang II increased collagen synthesis accompanied by an increase in expression of tissue inhibitor of metalloproteinase (TIMP)-1, and these increases were inhibited by valsartan, an AT1 receptor blocker, but augmented by PD123319, an AT2 receptor antagonist. Ang II decreased basal and IGF-I-induced collagen production and inhibited TIMP-1 expression in neonatal skin fibroblasts prepared from AT1a knockout (KO) mice. These Ang II-mediated inhibitory effects on collagen production and TIMP-1 expression observed in AT1a KO fibroblasts were attenuated by the addition of PD123319 or a tyrosine phosphatase inhibitor, sodium orthovanadate, but not affected by a serine/threonine phosphatase inhibitor, okadaic acid. Moreover, we demonstrated that transfection of a catalytically inactive, dominant negative SHP-1 (Src homology 2-containing protein-tyrosine phosphatase-1) mutant inhibited the Ang II-mediated inhibitory effect on both collagen synthesis and TIMP-1 expression in AT1a KO fibroblasts. These results suggest that AT1a receptor stimulation increases collagen production in skin fibroblasts at least in part due to the inhibition of collagen degradation via the increase in TIMP-1 expression, whereas AT2 receptor stimulation exerts inhibitory effects on TIMP-1 expression, which is mediated at least partially by the activation of SHP-1, thereby possibly inhibiting collagen production.
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PMID:Regulation of collagen synthesis in mouse skin fibroblasts by distinct angiotensin II receptor subtypes. 1455 Dec 24