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Modulation of MLC-2v gene expression by AP-1: complex regulatory role of Jun in cardiac myocytes
S K Goswami1, S Shafiq, M A Siddiqui
1Center for Cardiovascular and Muscle Research and the Department of Anatomy and Cell Biology, State University of New York Health Science Center at Brooklyn, 11203, USA.
Abstract:
Hypertrophic stimulation of cardiac myocytes results in rapid induction of a number of transcription factors, including members of the AP-1 family, which is followed by a programmed alteration in the pattern of gene expression. In the ventricular cardiocytes there is re-expression of the fetal atrial natriuretic factor (ANF) gene and upregulation of its myosin light chain-2 (MLC-2v). The mechanism(s) by which the induction ofAP-1 is coupled to the promoters of these target genes is largely unknown. In this report, we demonstrate that in transient co-transfection assay, c-Jun inhibited while Jun B stimulated the MLC-2v promoter activity. Mutant c-Jun recombinants, in which the activation domains were deleted, still remained inhibitory, but a specific mutation in the leucine zipper, which changes the alignment of Jun with its dimerization partner, caused a reversal of its effect on the target MLC-2v promoter. Based on these findings, we propose that in chicken cardiac myocytes, the regulation of MLC-2v promoter by Jun may occur via its interaction with other proteins, possibly of the leucine zipper family.
Insights
Jun proteins regulate gene expression in cardiac cells. This study shows Jun proteins interact with other factors to control myosin light chain-2v (MLC-2v) gene activity in chicken heart cells.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Gene Regulation
Background:
- Hypertrophic stimulation of cardiac myocytes induces transcription factors like AP-1.
- This leads to altered gene expression, including atrial natriuretic factor (ANF) and myosin light chain-2v (MLC-2v) in ventricular cardiocytes.
- The precise mechanisms linking AP-1 induction to target gene promoters are not fully understood.
Purpose of the Study:
- To investigate the role of Jun transcription factors in regulating the MLC-2v promoter.
- To elucidate the interaction mechanisms between Jun proteins and the MLC-2v promoter in chicken cardiac myocytes.
Main Methods:
- Transient co-transfection assays were performed.
- The effects of wild-type and mutant c-Jun and Jun B on the MLC-2v promoter activity were analyzed.
- Mutations targeted the activation domains and the leucine zipper region of c-Jun.
Main Results:
- c-Jun inhibited MLC-2v promoter activity, while Jun B stimulated it.
- Deletion of c-Jun activation domains retained inhibitory function.
- A specific mutation in the c-Jun leucine zipper reversed its inhibitory effect, suggesting protein-protein interactions are crucial.
Conclusions:
- Jun proteins differentially regulate the MLC-2v promoter in chicken cardiac myocytes.
- The interaction of Jun proteins with dimerization partners or other proteins, potentially via the leucine zipper, is critical for MLC-2v gene regulation.
- These findings provide insight into the molecular mechanisms controlling cardiac gene expression during hypertrophic stimulation.