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Effect of cyclosporin A treatment on the in vivo regulation of type I MHC gene expression.
J Appl Physiol (1985). 2004 Aug; 97(2):475-83.JA

Abstract

Rat soleus muscle consists predominantly of slow type I fibers. We have shown previously through deletion analysis that the highest level of reporter activity that we measure when injecting type I myosin heavy chain (MHC) promoter (MHC(1))-linked luciferase plasmid into soleus muscles depends on the presence of a 550-bp upstream enhancer (3,450-2,900) region of the promoter. Because the calcineurin-nuclear factor of activated T cells (NFAT) pathway has been implicated in the regulation of the slow muscle gene program, particularly the MHC(1) isoform, and the MHC(1) promoter contains several putative NFAT sites, we examined via deletion and mutation analyses whether this pathway is involved in the regulation of promoter activity in soleus. Nine days of treatment with the calcineurin inhibitor cyclosporin A (CsA) caused a significant decrease in activity of the -3,500- and -3,450-bp promoters compared with vehicle-treated rats. Truncation of the promoter to -2,900 bp or smaller reduced the activity and also eliminated the CsA responsiveness, thus implying that the enhancer region is required for CsA responsiveness. Surprisingly, mutating the two NFAT elements within the enhancer region had no obvious effect on promoter activity. CsA treatment resulted in an increase in the mRNA levels of fast-type IIa and IIx MHC isoforms, but RT-PCR analysis of MHC(1) pre-mRNA and mature mRNA expression in soleus muscles revealed no differences between vehicle- and CsA-treated rats. Although CsA affects the activity of the MHC(1) promoter, it appears that its effect is not through direct binding of NFAT to sites on the promoter.

Authors+Show Affiliations

Department of Physiology & Biophysics, University of California, Irvine, D-328, Med Sci I, Irvine, CA 92697, USA. jmeehan@uci.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15247194

Citation

Giger, Julia M., et al. "Effect of Cyclosporin a Treatment On the in Vivo Regulation of Type I MHC Gene Expression." Journal of Applied Physiology (Bethesda, Md. : 1985), vol. 97, no. 2, 2004, pp. 475-83.
Giger JM, Haddad F, Qin AX, et al. Effect of cyclosporin A treatment on the in vivo regulation of type I MHC gene expression. J Appl Physiol (1985). 2004;97(2):475-83.
Giger, J. M., Haddad, F., Qin, A. X., & Baldwin, K. M. (2004). Effect of cyclosporin A treatment on the in vivo regulation of type I MHC gene expression. Journal of Applied Physiology (Bethesda, Md. : 1985), 97(2), 475-83.
Giger JM, et al. Effect of Cyclosporin a Treatment On the in Vivo Regulation of Type I MHC Gene Expression. J Appl Physiol (1985). 2004;97(2):475-83. PubMed PMID: 15247194.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of cyclosporin A treatment on the in vivo regulation of type I MHC gene expression. AU - Giger,Julia M, AU - Haddad,Fadia, AU - Qin,Anqi X, AU - Baldwin,Kenneth M, PY - 2004/7/13/pubmed PY - 2005/1/15/medline PY - 2004/7/13/entrez SP - 475 EP - 83 JF - Journal of applied physiology (Bethesda, Md. : 1985) JO - J Appl Physiol (1985) VL - 97 IS - 2 N2 - Rat soleus muscle consists predominantly of slow type I fibers. We have shown previously through deletion analysis that the highest level of reporter activity that we measure when injecting type I myosin heavy chain (MHC) promoter (MHC(1))-linked luciferase plasmid into soleus muscles depends on the presence of a 550-bp upstream enhancer (3,450-2,900) region of the promoter. Because the calcineurin-nuclear factor of activated T cells (NFAT) pathway has been implicated in the regulation of the slow muscle gene program, particularly the MHC(1) isoform, and the MHC(1) promoter contains several putative NFAT sites, we examined via deletion and mutation analyses whether this pathway is involved in the regulation of promoter activity in soleus. Nine days of treatment with the calcineurin inhibitor cyclosporin A (CsA) caused a significant decrease in activity of the -3,500- and -3,450-bp promoters compared with vehicle-treated rats. Truncation of the promoter to -2,900 bp or smaller reduced the activity and also eliminated the CsA responsiveness, thus implying that the enhancer region is required for CsA responsiveness. Surprisingly, mutating the two NFAT elements within the enhancer region had no obvious effect on promoter activity. CsA treatment resulted in an increase in the mRNA levels of fast-type IIa and IIx MHC isoforms, but RT-PCR analysis of MHC(1) pre-mRNA and mature mRNA expression in soleus muscles revealed no differences between vehicle- and CsA-treated rats. Although CsA affects the activity of the MHC(1) promoter, it appears that its effect is not through direct binding of NFAT to sites on the promoter. SN - 8750-7587 UR - https://www.unboundmedicine.com/medline/citation/15247194/Effect_of_cyclosporin_A_treatment_on_the_in_vivo_regulation_of_type_I_MHC_gene_expression_ L2 - https://journals.physiology.org/doi/10.1152/japplphysiol.00763.2003?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -