Cardiac MHC gene expression: more complexity and a step forward

Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 02/2008; 294(1):H14-5. DOI: 10.1152/ajpheart.01297.2007
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Available from: John G Edwards, Nov 07, 2014
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    ABSTRACT: The CBP and p300 proteins are transcriptional co-activators that are involved in a variety of transcriptional pathways in development and in response to specific signaling pathways. We have previously demonstrated that the ability of both these factors to stimulate transcription is greatly enhanced by treatment of cardiac cells with the hypertrophic agent phenylephrine (PE). Here, we show that inhibition of either CBP or p300 with antisense or dominant negative mutant constructs inhibits PE-induced hypertrophy as assayed by atrial naturetic protein production, cardiac cell protein:DNA ratio and cell size. Furthermore, we show that overexpression of CBP or p300 can induce hypertrophy and that this effect requires their histone acetyltransferase (HAT) activity. Moreover, we show that PE can directly enhance CBP HAT activity and that artificial enhancement of HAT activity is sufficient to induce hypertrophy. Hence, CBP and p300 play an essential role in hypertrophy induced by PE, and this effect is mediated via PE-induced enhancement of their HAT activity. This is the first time a role for these factors, and their HAT activity, in hypertrophy has been directly demonstrated.
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    ABSTRACT: Thyroid hormones are thought to modulate gene expression positively or negatively through interactions with chromatin-associated receptors. Recently, the c-erb A proto-oncogene products have been shown to be nuclear thyroid hormone (T3) receptors (TR) by sequence similarity with other steroid receptors and by their ability to bind thyroid hormone. But it has not been shown that these receptors directly activate transcription of the responsive genes in vivo. In addition, the rat TR alpha gene encodes several messenger RNA (mRNA) species, generated by differential processing of its transcripts (ref. 22). For these reasons we investigated the ability of two major isoforms of the rat TR alpha gene products to activate transcription of a sarcomeric myosin heavy chain (mHC) gene, because expression of all members of this gene family is responsive to T3. We show here that the rTR alpha 1 receptor is a thyroid hormone-dependent transcriptional factor, which upon binding the T3 responsive element of the alpha-mHC gene, activates expression of this gene in vivo. The rTR alpha 2 isoform, which is identical to rTR alpha 1 except for its carboxyl terminal portion, is generated by alternative splicing of the rTR alpha gene transcript. This peptide, when produced in vitro and in vivo failed to bind T3 or other hormones or to trans-activate alpha-mHC gene expression. Thus, alternative splicing can produce marked differences in the functional properties of a transcriptional factor.
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    ABSTRACT: Transcriptional thyroid hormone responsiveness of the cardiac alpha-myosin heavy chain (alpha-MHC) gene has been demonstrated in transfections into fetal and neonatal cardiomyocytes and in transgenic mice. However, the correspondence between the regulation of MHC expression in dissociated cells with that in the intact heart is unclear. Given the cost and time involved in generating multiple transgenic lines for the characterization of gene regulatory elements, we used direct cardiac gene transfer to identify elements regulating both basal and thyroid hormone responsive cardiac alpha-MHC gene expression in the adult heart in vivo. Sequences upstream of the rat alpha-MHC gene linked to a luciferase reporter gene were injected into the hearts of adult rats subjected to various thyroid manipulations. The 161-bp sequence upstream of the transcription start site, which contains a TATA box, a CCAATT box, and a thyroid hormone response element, was transcriptionally active but not thyroid hormone responsive. The expression of a construct containing 388 bp of upstream sequence was increased by thyroid hormone administration, a response that required an intact thyroid hormone response element. However, expression of this construct failed to decrease to basal levels in a hypothyroid state. To confer complete (positive and negative) thyroid hormone regulation, 2,936 bp of upstream sequence was sufficient. These results demonstrate that, although necessary, the thyroid hormone response element is not sufficient for complete thyroid hormone regulation of this gene in vivo. In addition, DNA sequences regulating the quantitative expression of cardiac alpha-MHC in the euthyroid state have been demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
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