Potential role of helix-loop-helix proteins in cardiac gene expression.

Evans, Sylvia M.; Walsh, B A; Newton, Crystallee; Thorburn, Jacqueline; Gardner, Paul; Bilsen, Marc van

doi:10.1161/01.res.73.3.569

Cited by 21 publications

(10 citation statements)

References 45 publications

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“…In addition, forced expression of Id has been shown to inhibit tissue-specific gene expression or differentiation of a variety of cell types (1, 10 -12). Previous reports have demonstrated that Id levels are high in embryonic hearts and decrease after birth (13)(14)(15). Such a shift in Id expression is consistent with its role as an inhibitor of differentiation.…”

supporting

confidence: 78%

Expression of Id1 Results in Apoptosis of Cardiac Myocytes through a Redox-dependent Mechanism

Tanaka

Pracyk

Takeda

et al. 1998

Journal of Biological Chemistry

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We have constructed a recombinant adenovirus (Ad.Id1) that allows for efficient expression of the helixloop-helix protein Id1. After infection with Ad.Id1, neonatal cardiac myocytes display a significant reduction in viability, which was proportional to the level of Id1 expression. A similar effect was observed in adult myocytes. Morphological and biochemical assays demonstrated that Id1 expression resulted in myocyte apoptosis. In contrast, expression of Id1 in endothelial cells, vascular smooth muscle cells, or fibroblasts did not affect the viability of these cells. Along with the induction of apoptosis, the expression of Id1 in neonatal cardiac myocytes resulted in an increase in the level of intracellular reactive oxygen species. The source of these reactive oxygen species appears to be the mitochondria. Reducing the ambient oxygen concentration or treatment with a cell-permeant H 2 O 2 scavenger prevented Id1-stimulated apoptosis in cardiac myocytes. These results suggest that the expression of Id1 leads to the induction of apoptosis in cardiac myocytes through a redox-dependent mechanism.The Id family of proteins belongs to a class of nuclear proteins known as helix-loop-helix (HLH) 1 proteins, which regulate differentiation and tissue-specific gene expression. To date, four different Id family members have been identified (1-6). Although these four proteins share a high degree of homology, especially within the HLH domain, evidence suggests that they exert nonoverlapping functions (7-9).The HLH domain acts as a protein dimerization motif. Members of the HLH protein family which act to regulate transcription positively also contain an additional basic domain that mediates binding to DNA. In contrast, members of the Id family lack this domain and therefore are unable to bind DNA. These structural differences have led to a model in which Id proteins act in a dominant negative fashion to inhibit differentiation (1, 2). Under these circumstances, expression of high levels of Id1 would result in the binding and subsequent inactivation of basic domain HLH proteins.Consistent with this model of Id function is the observation that Id expression decreases when skeletal muscle cells differentiate (10). In addition, forced expression of Id has been shown to inhibit tissue-specific gene expression or differentiation of a variety of cell types (1, 10 -12). Previous reports have demonstrated that Id levels are high in embryonic hearts and decrease after birth (13-15). Such a shift in Id expression is consistent with its role as an inhibitor of differentiation. Although Id expression is low or absent in adult cardiac myocytes in culture, its expression can be reactivated by certain stimuli, such as ␣-adrenergic agonists (14, 15). A similar induction of Id expression has been demonstrated in skeletal muscle after treatment with the cardiotoxic chemotherapeutic agent doxorubicin (16,17).Although previous studies have demonstrated that forced expression of Id proteins can block differentiation, relatively little is known a...

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supporting

confidence: 78%

Expression of Id1 Results in Apoptosis of Cardiac Myocytes through a Redox-dependent Mechanism

Tanaka

Pracyk

Takeda

et al. 1998

Journal of Biological Chemistry

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“…These include genes involved in sarcomeric function, 23,25 like ␣-actin, troponin I, and myosin light chain 2, as well as a number of genes involved in ATP production, 26 including a heart-and muscle-specific isoform of ADP/ATP translocase, the Reiske iron-sulfur protein (a ubiquitously expressed electron transport chain component), and a muscle isozyme of phosphofructokinase. The precise molecular mechanism underlying this inhibition of gene transcription is unknown but has been suggested to be linked to a reduction of myoD activity 27 ; however, studies from Evans et al 28 indicate that overexpression of Id, a suppressor of myoD activity, in cardiac myocytes does not result in significant suppression of the ANP gene promoter, implying that the mechanism underlying doxorubicin-dependent inhibition of this gene may be distinct from that governing inhibition of other myogenic proteins.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes

1999

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Abstract-Doxorubicin is an antineoplastic agent with significant cardiotoxicity. We examined the effects of this agent on the expression of the natriuretic peptide (NP) genes in cultured neonatal rat atrial myocytes. Doxorubicin suppressed NP secretion, steady-state NP mRNA levels, and NP gene promoter activity. In each instance, brain NP (BNP) proved to be more sensitive than atrial NP (ANP) to the inhibitory effects of the drug. ICRF-187 and probucol reversed the inhibition by doxorubicin of ANP mRNA accumulation and ANP gene promoter activity while exerting no effect on BNP mRNA levels or promoter activity. This represents the first identification of the NP genes as targets of doxorubicin toxicity in the myocardial cell. This inhibition operates predominantly at a transcriptional locus and has more potent effects on BNP versus ANP secretion/gene expression.

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“…In transient assays, the MLC-2v promoter is not downregulated by cotransfection with an Id expression vector that negatively regulates the activity of E-box-dependent promoters in the cardiac and skeletal muscles (21). Taken together, there is increasing evidence that cardiac muscle specificity for the MLC-2v promoter does not rely on a single site and requires combinatorial interactions between a variety of regulatory elements located within the 250-bp MLC-2v promoter fragment.…”

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confidence: 99%

“…Given the central role of a family of basic helix-loop-helix (HLH) myogenic determination genes (the MyoD, myf-5, myogenin, and myf-6/MRF4/herculin genes) in skeletal myogenesis, a number of laboratories have examined the potential role of basic HLH proteins in the control of cardiac myogenesis. Cardiac muscle cells express the ubiquitous basic HLH protein E12/E47 and are permissive for the actions of MyoD (21,33). Furthermore, a number of cardiac promoters have been documented to acquire an intact E-box site to maintain optimal activity in transient assays in cultured cardiac muscle cells (35).…”

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confidence: 99%

The basic helix-loop-helix protein upstream stimulating factor regulates the cardiac ventricular myosin light-chain 2 gene via independent cis regulatory elements.

et al. 1994

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Previous studies have documented that 250 bp of the rat cardiac ventricular myosin light-chain 2 (MLC-2v) promoter is sufficient to confer cardiac muscle-specific expression on a luciferase reporter gene in both transgenic mice and primary cultured neonatal rat myocardial cells. Utilizing ligation-mediated PCR to perform in vivo dimethyl sulfate footprinting, the present study has identified protein-DNA interaction within the position from -176 to -165. This region, identified as MLE1, contains a core sequence, CACGTG, which conforms to the consensus E-box site and is identical to the upstream stimulating factor (USF)-binding site of the adenovirus major late promoter. Transient assays of luciferase reporter genes containing point mutations of the site demonstrate the importance of this cis regulatory element in the transcriptional activation of this cardiac muscle gene in ventricular muscle cells. The protein complex that occupies this site is capable of binding to HF-la and PRE B sites which are known to be required for cardiac muscle-specific expression of rat MLC-2v and a-myosin heavy-chain genes, respectively. This study provides direct evidence that USF, a member of the basic helix-loop-helix leucine zipper family, binds to MLE1, HF-la, and PRE B sites and suggests that it is a component of protein complexes that may coordinately control the expression of MLC-2v and a-myosin heavy-chain genes. The current study also provides evidence that USF can positively and negatively regulate the MLC-2v gene via independent cis regulatory elements.

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Potential role of helix-loop-helix proteins in cardiac gene expression.

Cited by 21 publications

References 45 publications

Expression of Id1 Results in Apoptosis of Cardiac Myocytes through a Redox-dependent Mechanism

Expression of Id1 Results in Apoptosis of Cardiac Myocytes through a Redox-dependent Mechanism

Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes

The basic helix-loop-helix protein upstream stimulating factor regulates the cardiac ventricular myosin light-chain 2 gene via independent cis regulatory elements.

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