Microribonucleic acid-21 increases aldosterone secretion and proliferation in H295R human adrenocortical cells.
ABSTRACT MicroRNAs (miRNAs) are endogenous small noncoding RNAs that decrease the expression levels of specific genes by translational repression, sequestration, and degradation of their mRNAs. Angiotensin II is an important modulator of adrenal zona glomerulosa cell physiology, including steroidogenesis and proliferation among many other physiological processes. Because each miRNA may regulate the expression levels of multiple genes, thereby resembling the transcription regulatory networks triggered by transcription factors, we hypothesize that specific miRNAs may be involved in angiotensin II-mediated adrenocortical cell physiology. The human adrenocortical cell line H295R is the only adrenal cell line available with a steroid secretion pattern and regulation similar to freshly isolated adrenocortical cells. We screened for miRNAs regulated by angiotensin II in H295R cells and found that miRNA-21 expression levels were specifically modulated by angiotensin II. Angiotensin II time dependently increased miRNA-21 expression reaching a 4.4-fold induction after 24 h. Angiotensin II-mediated miRNA-21 expression resulted in biologically active miRNA-21, determined using a fusion mRNA reporter system carrying miRNA-21 target sequences in its 3' untranslated region. Up-regulation of miRNA-21 intracellular levels increased aldosterone secretion but not cortisol. Elevation of miRNA-21 levels also increased cell proliferation in H295R cells. In summary, miRNA-21 is an endogenously expressed miRNA in human adrenal cells. miRNA-21 expression is up-regulated by angiotensin II, and its overexpression caused an increase in aldosterone secretion and cell proliferation. Alterations in miRNA-21 expression levels or function may be involved in dysregulation of angiotensin II signaling and abnormal aldosterone secretion by adrenal glands in humans.
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ABSTRACT: The C. elegans heterochronic gene pathway consists of a cascade of regulatory genes that are temporally controlled to specify the timing of developmental events. Mutations in heterochronic genes cause temporal transformations in cell fates in which stage-specific events are omitted or reiterated. Here we show that let-7 is a heterochronic switch gene. Loss of let-7 gene activity causes reiteration of larval cell fates during the adult stage, whereas increased let-7 gene dosage causes precocious expression of adult fates during larval stages. let-7 encodes a temporally regulated 21-nucleotide RNA that is complementary to elements in the 3' untranslated regions of the heterochronic genes lin-14, lin-28, lin-41, lin-42 and daf-12, indicating that expression of these genes may be directly controlled by let-7. A reporter gene bearing the lin-41 3' untranslated region is temporally regulated in a let-7-dependent manner. A second regulatory RNA, lin-4, negatively regulates lin-14 and lin-28 through RNA-RNA interactions with their 3' untranslated regions. We propose that the sequential stage-specific expression of the lin-4 and let-7 regulatory RNAs triggers transitions in the complement of heterochronic regulatory proteins to coordinate developmental timing.Nature 03/2000; 403(6772):901-6. · 36.28 Impact Factor