Regulation of expression of the genes encoding steroidogenic enzymes in the ovary.
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Biomedical subjects
M Kilgore
Publications and source records attributed to M Kilgore.
Regulation of expression of the genes encoding steroidogenic enzymes.
In recent years it has become apparent that tropic hormones involved in steroidogenesis act to regulate the expression of the enzymes involved in the various steroidogenic pathways. This is particularly evident in the ovary where the episodic secretion of steroids throughout the ovarian cycle is regulated largely by changes in the levels of the particular enzymes involved in each step of the steroid biosynthetic pathways. Recently, the genes for the various cytochrome P450 species involved in ovarian steroidogenesis, namely cholesterol side-chain cleavage P450 (P450SCC), 17 alpha-hydroxylase P450 (P450(17 alpha], and aromatase cytochrome P450 (P450AROM) have been isolated and characterized, making it possible to study the regulation of expression at the molecular level. To this end, a series of chimeric constructs have been prepared in which fragments of the 5'-untranslated region of bovine P450(17 alpha) and P450SCC have been inserted upstream of the chloramphenicol acetyl transferase (CAT) and beta-globin reporter genes. These constructs have been used to transfect primary cultures of bovine luteal and thecal cells. The results indicate that cAMP responsiveness lies within defined regions of genes which do not contain a classical CRE, similar to previous results utilizing adrenal cells in culture. Furthermore, although constructs containing both the P450(17 alpha) and P450SCC 5'-upstream regions are expressed in both luteal and thecal cell cultures, only those containing the P450SCC sequences are expressed in luteal cells. Studies on the expression of P450AROM indicate that the promoter which is responsible for its expression in human placenta is not operative in the corpus luteum. Thus estrogen biosynthesis may be regulated by the differential use of tissue specific promoters, thus accounting for the complexity and multifactorial nature of the expression of this activity.
Animals↗
The aromatase enzyme: from cloning to cancer.
Estrogen production by adipose tissue has been implicated in the etiology of such human cancers as endometrial and breast cancer. Estrogen production by adipose cells is subject to complex multifactorial regulation by a number of growth factors and cytokines, including those produced by breast cancer cells. In order to understand the mechanisms responsible for aromatase regulation, the structural gene encoding aromatase cytochrome P-450 (P-450AROM) was isolated from human genomic DNA. The gene spans at least 70 kb and is comprised of 10 exons, the first of which is untranslated. DNA sequence analysis indicates that the gene has a putative TATA (ATAAAA) sequence at -23 bp and putative CAAT binding sequences beginning at -41, -67, and -83 bp, that constitute a promoter region responsible for expression in placenta. However, this promoter does not appear to be responsible for expression in adipose, which may therefore be under the control of another, tissue-specific, promoter. Use of Polymerase Chain Reaction (PCR) technology has allowed for determination of expression of P-450AROM in samples of breast adipose. Preliminary results indicate that expression is highest in the upper lateral region, similar to the site of most frequent localization of tumors.
Adipose Tissue↗
Electroencephalographic change in Parkinsonian patients treated with levodopa-carbidopa.
Our findings in a relatively small series of cases seem to confirm a lack of statistically significant EEG changes when Carbidopa is combined with Levodopa in the therapy of patients with Parkinson's disease. There appears to be a slight increase in basic background frequency which was one of the earlier findings when Levodopa was first used clinically. From the literature surveyed there appears to be a definite lack of consistency in the effects of Levodopa therapy on the electroencephalogram and on the clinical status of the patients followed. We think this well may be explainable by the fact that no large study has been accomplished in which a neuroanatomical (pathological) correlation has been done with both the clinical and the EEG data. Neurological examination and the electroencephalogram are both clinical tools and have yet to be closely reviewed with the added parameter of neuro-pathologic investigation in this new day of therapy for Parkinson's disease.
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