Molecular Cloning of a Novel Thyroid Hormone-responsive Gene,  , in Human Skin Fibroblasts

Miyazaki, Takashi; Kanou, Yasuhiko; Murata, Yoshiharu; Ohmori, Sachiko; Niwa, Toshimitsu; Maeda, Kenji; Yamamura, Hideki; Seo, Hisao

doi:10.1074/jbc.271.24.14567

Cited by 74 publications

(74 citation statements)

References 21 publications

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“…Therefore, we suggest that ''modulatory'' calcineurin-interacting protein may be a more appropriate term. Two other members of the MCIP gene family, MCIP2 and MCIP3, are not located on chromosome 21 (13,14). MCIP1 and MCIP2 are expressed at the highest levels in striated muscles and brain, whereas MCIP3 is expressed at a low level in a broad range of tissues.…”

mentioning

confidence: 99%

Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy

Vega

Rothermel

Weinheimer

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

206

173

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The calcium͞calmodulin-dependent protein phosphatase calcineurin stimulates cardiac hypertrophy in response to numerous stimuli. Calcineurin activity is suppressed by association with modulatory calcineurin-interacting protein (MCIP)1͞DSCR1, which is up-regulated by calcineurin signaling and has been proposed to function in a negative feedback loop to modulate calcineurin activity. To investigate the involvement of MCIP1 in cardiac hypertrophy in vivo, we generated MCIP1 null mice and subjected them to a variety of stress stimuli that induce cardiac hypertrophy. In the absence of stress, MCIP1 ؊/؊ animals exhibited no overt phenotype. However, the lack of MCIP1 exacerbated the hypertrophic response to activated calcineurin expressed from a musclespecific transgene, consistent with a role of MCIP1 as a negative regulator of calcineurin signaling. Paradoxically, however, cardiac hypertrophy in response to pressure overload or chronic adrenergic stimulation was blunted in MCIP1 ؊/؊ mice. These findings suggest that MCIP1 can facilitate or suppress cardiac calcineurin signaling depending on the nature of the hypertrophic stimulus. These opposing roles of MCIP have important implications for therapeutic strategies to regulate cardiac hypertrophy through modulation of calcineurin-MCIP activity.

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mentioning

confidence: 99%

Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy

Vega

Rothermel

Weinheimer

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

206

173

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“…Individuals trisomic for this region, which is estimated to encode 50 -100 different proteins, display features of the Down syndrome phenotype. ZAKI-4 was identified from a human fibroblast cell line in a screen for genes that are transcriptionally activated in response to thyroid hormone (26). We were stimulated by these observations to undertake a detailed analysis of the proteins encoded by these genes with respect to calcineurin signaling in mammalian cells.…”

mentioning

confidence: 99%

A Protein Encoded within the Down Syndrome Critical Region Is Enriched in Striated Muscles and Inhibits Calcineurin Signaling

Rothermel

Vega

Yang

et al. 2000

Journal of Biological Chemistry

380

341

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Here we describe a small family of proteins, termed MCIP1 and MCIP2 (for myocyte-enriched calcineurin interacting protein), that are expressed most abundantly in striated muscles and that form a physical complex with calcineurin A. MCIP1 is encoded by DSCR1, a gene located in the Down syndrome critical region. Expression of the MCIP family of proteins is up-regulated during muscle differentiation, and their forced overexpression inhibits calcineurin signaling to a muscle-specific target gene in a myocyte cell background. Binding of MCIP1 to calcineurin A requires sequence motifs that resemble calcineurin interacting domains found in NFAT proteins. The inhibitory action of MCIP1 involves a direct association with the catalytic domain of calcineurin, rather than interference with the function of downstream components of the calcineurin signaling pathway. The interaction between MCIP proteins and calcineurin may modulate calcineurin-dependent pathways that control hypertrophic growth and selective programs of gene expression in striated muscles.Calcineurin is a serine/threonine protein phosphatase that plays a pivotal role in developmental and homeostatic regulation of a wide variety of cell types (1, 2). The interaction of calcineurin with transcription factors of the NFAT 1 family following activation of the T cell receptor in leukocytes provides the best characterized example of how calcineurin regulates gene expression (3). Changes in intracellular calcium promote binding of Ca 2ϩ /calmodulin to the catalytic subunit of calcineurin (CnA), thereby displacing an autoinhibitory region and allowing access of protein substrates to the catalytic domain. Dephosphorylation of NFAT by activated calcineurin promotes its translocation from the cytoplasm to the nucleus, where NFAT binds DNA cooperatively with an AP1 heterodimer to activate transcription of genes encoding cytokines such as IL-2. This basic model of NFAT activation has been shown to transduce Ca 2ϩ signals via calcineurin in many cell types and to control transcription of diverse sets of target genes unique to each cellular environment (4). In each case, NFAT acts cooperatively with other transcription factors that include proteins of the AP1 (3), cMAF (5), GATA (6 -8), or MEF2 (9 -12) families. In addition to T cell activation, cellular responses controlled by calcineurin signaling include synaptic plasticity (11,13,14) and apoptosis (15,16).Recent studies of calcineurin signaling in striated myocytes of heart and skeletal muscle have expanded the scope of important physiological and pathological events controlled by this ubiquitously expressed protein. Forced expression of a constitutively active form of calcineurin in hearts of transgenic mice promotes cardiac hypertrophy that progresses to dilated cardiomyopathy, heart failure, and death, in a manner that recapitulates features of human disease (7). Moreover, hypertrophy and heart failure in these animals, and in certain other animal models of cardiomyopathy, are prevented by administration of the calcin...

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“…Calcineurin is known to mediate important functions of the brain, such as neuronal apoptosis, amyloid b-peptide formation, synaptic plasticity and memory [reviewed in 25]. Since we have previously shown that ZAKI-4 mRNA is expressed in the human brain, as well as in heart and skeletal muscles [18], we hypothesize that ZAKI-4 proteins play a crucial role in those tissues by inhibiting calcineurin activity.…”

Section: Introductionmentioning

confidence: 98%

“…ZAKI-4 proteins (also designated as DSCR1L1 by the Human Nomenclature Committee) are products of the ZAKI-4 gene which we previously identified as a thyroid hormoneresponsive gene from cultured human skin fibroblasts [18]. In human fibroblasts, the transcription of the ZAKI-4 gene is markedly enhanced by physiological concentrations of 3,3'5-triiodothyronine (T 3 ), an active form of thyroid hormone; however, the enhancement is not direct and requires de novo protein synthesis [18].…”

Section: Introductionmentioning

confidence: 99%

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Spatial and Intracellular Distribution of the Endogenous Calcineurin-Inhibitory Proteins, ZAKI-4, in Mouse Brain

Hoshino

Takagishi

Kanou

et al. 2004

Acta Histochem. Cytochem

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Molecular Cloning of a Novel Thyroid Hormone-responsive Gene, , in Human Skin Fibroblasts

Cited by 74 publications

References 21 publications

Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy

Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy

A Protein Encoded within the Down Syndrome Critical Region Is Enriched in Striated Muscles and Inhibits Calcineurin Signaling

Spatial and Intracellular Distribution of the Endogenous Calcineurin-Inhibitory Proteins, ZAKI-4, in Mouse Brain

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