TY - JOUR
T1 - Differential regulation of respiratory chain subunits by a CREB-dependent signal transduction pathway
T2 - Role of cyclic AMP in cytochrome c and COXIV gene expression
AU - Gopalakrishnan, Lekha
AU - Scarpulla, Richard C.
N1 - Copyright:
Copyright 2004 Elsevier B.V., All rights reserved.
PY - 1994/1/7
Y1 - 1994/1/7
N2 - In vertebrate organisms, the molecular mechanisms by which extracellular signals regulate mitochondrial function and biogenesis are largely unknown. We have previously identified multiple cis-acting elements in both cytochrome c and cytochrome oxidase subunit IV (COXIV) genes that are likely targets for the regulated expression of respiratory chain components. We now demonstrate that cytochrome c but not COXIV mRNA is induced by cAMP through a mechanism involving transcriptional activation. Maximal induction occurs within 3 h and does not require de novo protein synthesis. The differential response of these genes is mediated by two distinct cAMP response elements (CREs) in the cytochrome c promoter region. Both elements function independently to drive cAMP-dependent expression from a heterologous promoter and within the proper cytochrome c promoter context. In addition, the binding properties of both elements to nuclear factors were characterized by competition DNase I footprinting, methylation interference footprinting, site-directed mutagenesis, and UV-induced DNA-protein cross-linking. The results are all consistent with the specific recognition of both CREs by CRE binding protein (CREB). A highly purified preparation of recombinant CREB formed a specific complex with each of the cytochrome c CREs identical to that formed with a crude nuclear fraction. In addition, the trans-activation of cytochrome c gene expression by recombinant CREB and protein kinase A in transfected cells was completely dependent on functional CREs within the promoter. These results establish that respiratory chain gene expression can be regulated directly by cAMP through a CREB-dependent signal transduction pathway.
AB - In vertebrate organisms, the molecular mechanisms by which extracellular signals regulate mitochondrial function and biogenesis are largely unknown. We have previously identified multiple cis-acting elements in both cytochrome c and cytochrome oxidase subunit IV (COXIV) genes that are likely targets for the regulated expression of respiratory chain components. We now demonstrate that cytochrome c but not COXIV mRNA is induced by cAMP through a mechanism involving transcriptional activation. Maximal induction occurs within 3 h and does not require de novo protein synthesis. The differential response of these genes is mediated by two distinct cAMP response elements (CREs) in the cytochrome c promoter region. Both elements function independently to drive cAMP-dependent expression from a heterologous promoter and within the proper cytochrome c promoter context. In addition, the binding properties of both elements to nuclear factors were characterized by competition DNase I footprinting, methylation interference footprinting, site-directed mutagenesis, and UV-induced DNA-protein cross-linking. The results are all consistent with the specific recognition of both CREs by CRE binding protein (CREB). A highly purified preparation of recombinant CREB formed a specific complex with each of the cytochrome c CREs identical to that formed with a crude nuclear fraction. In addition, the trans-activation of cytochrome c gene expression by recombinant CREB and protein kinase A in transfected cells was completely dependent on functional CREs within the promoter. These results establish that respiratory chain gene expression can be regulated directly by cAMP through a CREB-dependent signal transduction pathway.
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M3 - Article
C2 - 8276781
AN - SCOPUS:0028049078
SN - 0021-9258
VL - 269
SP - 105
EP - 113
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 1
ER -