Regulation of Na,K-ATPase β1 Subunit Gene Transcription by Low External Potassium in Cardiac Myocytes

Zhuang, Yong; Wendt, Christine; Gick, Gregory

doi:10.1074/jbc.m002953200

Cited by 16 publications

(20 citation statements)

References 47 publications

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“…Mutation of murine GC/GA elements within the cardiac troponin I promoter produces a four-to fivefold reduction of promoter activity comparable to that seen for the avian cTnT promoter. Putative Sp1 promoter elements have also been shown to be required for optimal activity of cardiac and skeletal ␣-actin, sarco(endo)plasmic Ca 2ϩ -ATPase, and Na ϩ -K ϩ -ATPase ␤ 1 -subunit genes in cultured cells (6,16,24,31,33). These studies do not show direct trans-activation of promoter constructs cotransfected with expressed Sp factors.…”

Section: Sp1 Activates the ϫ268ctnt Promotermentioning

confidence: 64%

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo

Azakie¹,

Fineman²

2006

American Journal of Physiology-Heart and Circulatory Physiology

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Azakie, Anthony, Jeffrey R. Fineman, and Youping He. Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo. Am J Physiol Heart Circ Physiol 291: H600 -H611, 2006. First published April 14, 2006; doi:10.1152/ajpheart.01305.2005.-Combinatorial interactions between cis elements and trans-acting factors are required for regulation of cardiac gene expression during normal cardiac development and pathological cardiac hypertrophy. Sp factors bind GC boxes and are implicated in recruitment and assembly of the basal transcriptional complex. In this study, we show that the cardiac troponin T (cTnT) promoter contains a GC box that is necessary for basal and cAMP-mediated activity of cTnT promoter constructs transfected in embryonic cardiomyocytes. Cardiac nuclear proteins bind the cTnT GC box in a sequence-specific fashion and consist of Sp1, Sp2, and Sp3 protein factors. By chromatin immunoprecipitation, Sp1 binds the cTnT promoter "in vivo." Cotransfected Sp1 trans-activates the cTnT promoter in cardiomyocytes in culture. Sp3 represses Sp1-mediated transcriptional activation of the cTnT gene in embryonic cardiomyocytes. Sp3 repression of Sp1-mediated cTnT promoter activation is dose dependent, inferring a mechanism of competitive binding/inhibition. To evaluate the role of Sp factors in cardiac gene expression in vivo, we have established a clinically relevant animal model of pathological cardiac hypertrophy where the fetal cardiac program is activated. In this animal model, cardiac hypertrophy results from increased left-right shunting, volume loading of the left ventricle, and pressure loading of the right ventricle. Sp1 expression is increased in all four hypertrophied cardiac chambers, whereas Sp3 expression is diminished. This observation is consistent with the in vitro activating function of Sp1 and inhibitory effects of Sp3 on activity of cTnT promoter constructs. Sp factor levels are modulated during the hypertrophic cardiac program in vivo. promoter function; transcription factors; cardiac differentiation; cell specification; cardiac muscle hypertrophy THE SP FAMILY OF TRANSCRIPTION factors is characterized by a series of three zinc fingers at the carboxy-terminal end of the protein that are preceded by glutamine-and serine-threoninerich domains (8, 28). Sp proteins bind GC boxes and the related GT/CACC-box motifs and are implicated in the recruitment and assembly of the basal transcriptional complex. GC boxes have been implicated in the regulation of cardiac promoters, but the direct effects of Sp family members on cardiac promoter activity have not been defined.We use the cardiac troponin T (cTnT) gene promoter as a model of cardiac-specific gene expression during myocardial differentiation (3,5,22,27,29). The cTnT promoter is developmentally regulated by numerous promoter motifs and transacting factors, including MCAT or transcription enhancer factor-1 (TEF-1) binding sites, AT-rich/monocyte enhancer factor-2 (MEF-2) bindin...

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Section: Sp1 Activates the ϫ268ctnt Promotermentioning

confidence: 64%

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo

Azakie¹,

Fineman²

2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…Some studies have suggested that potassium itself can modulate gene expression. Recently, the promoter of the Na ϩ -K ϩ -ATPase has been shown to be potassium responsive, such that low potassium concentrations cause an upregulation in the expression of this gene (39). It is therefore possible that in the rats fed the low-potassium diet there is an upregulation of gene expression in response to the low potassium levels and that this upregulation is effectively inhibited by the high-potassium diet.…”

Section: Discussionmentioning

confidence: 98%

A high-potassium diet reduces infarct size and improves vascular structure in hypertensive rats

Dorrance

Pollock

Romanko

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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High-potassium diets can improve vascular function, yet the effects of potassium supplementation on ischemic stroke have not been studied. We hypothesized that dietary potassium supplementation would reduce ischemic cerebral infarct size by reversing cerebral artery hypertrophy. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were fed diets containing 0.79% potassium (LK) or 2.11% potassium (HK) for 6 wk; Wistar-Kyoto (WKY) rats were fed the LK diet. The HK diet did not reduce blood pressure, as measured by telemetry, in the SHRSP. Cerebral ischemia was induced by middle cerebral artery (MCA) occlusion. The resultant infarct was smaller in the HK-SHRSP than in the LK-SHRSP: 55.1 +/- 6.3 vs. 71.4 +/- 2.4% of the hemisphere infarcted (P < 0.05). Infarcts were smaller in WKY rats (33.5 +/- 4.8%) than in LK-SHRSP or HK-SHRSP. The vessel wall of MCAs from LK-SHRSP was hypertrophied compared with WKY rats; this was reversed in HK-SHRSP. RT-PCR analysis of the cerebral vessels showed that expression of platelet-derived growth factor receptors-alpha and -beta, epidermal growth factor receptor, and collagen I and III was increased in the vessels from LK-SHRSP compared with WKY rats and reduced in HK-SHRSP. These results suggest that potassium supplementation provides neuroprotection in a model of ischemic stroke independent of blood pressure and possibly through changes in vascular structure.

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“…In poorly differentiated carcinoma cell lines, ␤-subunit expression is down-regulated by the Snail transcription factor (26). Furthermore, in cardiac myocytes, the ␤-subunit is regulated independently of the ␣-subunit by changes in external K (27). Both scenarios, and presumably others as well, could potentially result in the wild type ␣-subunit being synthesized in excess of the ␤-subunit protein.…”

Section: Discussionmentioning

confidence: 99%

Association with β-COP Regulates the Trafficking of the Newly Synthesized Na,K-ATPase*

Morton

Farr

Hull

et al. 2010

Journal of Biological Chemistry

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Plasma membrane expression of the Na,K-ATPase requires assembly of its ␣-and ␤-subunits. Using a novel labeling technique to identify Na,K-ATPase partner proteins, we detected an interaction between the Na,K-ATPase ␣-subunit and the coat protein, ␤-COP, a component of the COP-I complex. When expressed in the absence of the Na,K-ATPase ␤-subunit, the Na,K-ATPase ␣-subunit interacts with ␤-COP, is retained in the endoplasmic reticulum, and is targeted for degradation. In the presence of the Na,K-ATPase ␤-subunit, the ␣-subunit does not interact with ␤-COP and traffics to the plasma membrane.Pulse-chase experiments demonstrate that in cells expressing both the Na,K-ATPase ␣-and ␤-subunits, newly synthesized ␣-subunit associates with ␤-COP immediately after its synthesis but that this interaction does not constitute an obligate intermediate in the assembly of the ␣-and ␤-subunits to form the pump holoenzyme. The interaction with ␤-COP was reduced by mutating a dibasic motif at Lys 54 in the Na,K-ATPase ␣-subunit. This mutant ␣-subunit is not retained in the endoplasmic reticulum and reaches the plasma membrane, even in the absence of Na,K-ATPase ␤-subunit expression. Although the Lys 54 ␣-subunit reaches the cell surface without need for ␤-subunit assembly, it is only functional as an ion-transporting ATPase in the presence of the ␤-subunit.

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Regulation of Na,K-ATPase β1 Subunit Gene Transcription by Low External Potassium in Cardiac Myocytes

Cited by 16 publications

References 47 publications

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo

A high-potassium diet reduces infarct size and improves vascular structure in hypertensive rats

Association with β-COP Regulates the Trafficking of the Newly Synthesized Na,K-ATPase*

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