Multihormonal regulation of pro-opiomelanocortin gene expression.
Item
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Title
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Multihormonal regulation of pro-opiomelanocortin gene expression.
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Identifier
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AAI9304653
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identifier
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9304653
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Creator
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Dermer, Shari Joy.
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Contributor
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Adviser: James L. Roberts
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Date
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1992
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular | Biology, Neuroscience
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Abstract
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Modulation of POMC gene expression occurs in response to a variety of stimuli. The POMC gene is subject to negative steroid feedback in two different neuroendocrine systems; by glucocorticoids in the hypothalamic-pituitary-adrenal axis and by estrogens in a subset of neurons in the hypothalamus. Both of these regulatory patterns are due to the genomic action of steroid receptors. Estrogen-mediated regulation of POMC gene expression was studied utilizing a model POMC-expressing cell culture system that expresses an exogenous estrogen receptor. ER-1 cells produced functional estrogen receptor as assessed by nuclear steroid binding assays. Time-, dose-, and receptor-dependence of estrogen-mediated POMC gene regulation was studied utilizing solution hybridization/nuclease protection assays. There was a dose-dependent decrease in long term POMC gene expression. The response to estrogen treatment was a biphasic, characterized by a significant transient increase in POMC biosynthesis with acute treatment, followed by a sustained long term decrease in gene expression to below control levels. These events were determined to be estrogen receptor-dependent. The mechanism of estrogen-mediated POMC gene inhibition was compared to the effects of glucocorticoids by examining the interaction of estrogens and a positive effector, corticotropin releasing factor (CRF). It was found that both estrogen and glucocorticoid treatments attenuated the stimulatory effects of CRF in ER-1 cells. The potential involvement of c-fos gene expression in acute estrogen-mediated stimulation of POMC expression was explored. While it was demonstrated that estrogen treatment in ER-1 cells resulted in induction of c-fos, a cause and effect relationship remains speculative. Delineation of a sequence which was able to mediate CRF stimulation of a POMC reporter gene was performed using transient transfection studies. This sequence contains a nearly perfect palindromic element and may represent a binding site for a transcriptional regulatory protein. The complex array of regulation schemes which govern expression of the POMC gene require integration of signals from many different hormones, neurotransmitters, and second messengers. It is not surprising that this may involve interaction of multiple transcription factors that function within the context of the entire POMC promoter.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
