Regulation of GATA-4 and AP-1 in transgenic mice overexpressing cardiac calsequestrin.
Transgenic mouse hearts overexpressing the Ca(2+)-binding protein calsequestrin (CSQ) have an accompanying 10-fold increase in the sarcoplasmic reticulum (SR) Ca2+ load, however, exhibits slow and small Ca(2+)-induced Ca2+ release. Such slow kinetics of Ca2+ release may have activated excitation-transcription coupling as CSQ overexpressing hearts have induced levels of NFAT and GATA-4 activities and higher levels of c-fos mRNA and cFos protein compared to those of non-transgenic littermates. Adaptive responses, however, appear to downregulate transcriptional regulators controlling c-fos gene including serum response factor and Ca2+/cAMP response element-binding protein. CSQ-overexpressing hearts also had decreased levels of cJun protein, resulting in downregulated AP-1 activity. The mRNA levels of angiotensin II type1a receptor which requires AP-1 and GATA-4 for gene transcription was suppressed in CSQ overexpressing hearts. These results demonstrate that CSQ can regulate GATA-4- and AP-1-dependent transcriptional events, indicating the existence of SR-nuclear circuits of signal transduction in adult cardiac muscle.
Suzuki
Y J
YJ
Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA. suzuki_lp@hnrc.tufts.edu
Ikeda
T
T
Shi
S S
SS
Kitta
K
K
Kobayashi
Y M
YM
Morad
M
M
Jones
L R
LR
Blumberg
J B
JB
D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002155:Calsequestrin / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D050991:GATA4 Transcription Factor; D005786:Gene Expression Regulation; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004247:DNA