scholarly journals A Low-Affinity Serum Response Element Allows Other Transcription Factors To Activate Inducible Gene Expression in Cardiac Myocytes

1999 ◽  
Vol 19 (3) ◽  
pp. 1841-1852 ◽  
Author(s):  
Wirt A. Hines ◽  
Jacqueline Thorburn ◽  
Andrew Thorburn
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Consensus Sequence ◽  
Serum Response Element ◽  
Cardiac Muscle Cells ◽  
Response Element ◽  
Inducible Gene Expression ◽  
Hypertrophic Growth ◽  
Serum Response ◽  
Inducible Gene

ABSTRACT Hypertrophic growth of cardiac muscle cells is induced by a variety of physiological and pathological stimuli and is associated with a number of changes, including activation of genes such as atrial natriuretic factor. We found that two serum response element (SRE)-like DNA elements, one of which does not meet the consensus sequence and binds serum response factor (SRF) with low affinity, regulate the activity of this promoter. Surprisingly, the ability to induce the promoter by two different physiologic stimuli, as well as various activated transcription factors, including SRF-VP16, was primarily dependent upon the nonconsensus rather than the consensus SRE. This SRE controls the induction of gene expression via an unusual mechanism in that it is required to allow some, but not all, active transcription factors at unrelated sites on the promoter to stimulate gene expression. Thus, in addition to regulation of SRF activity by growth stimuli, regulation of a low-affinity SRE element controls inducible gene expression by modulating the ability of other transcription factors to stimulate the transcription machinery.

scholarly journals Voltage-insensitive Ca2+ channels and Ca2+/calmodulin-dependent protein kinases propagate signals from endothelin-1 receptors to the c-fos promoter.

1996 ◽  
Vol 16 (10) ◽  
pp. 5915-5923 ◽  
Author(s):  
Y Wang ◽  
M S Simonson
Keyword(s):  
Gene Expression ◽  
Protein Kinases ◽  
Ectopic Expression ◽  
Promoter Activation ◽  
Serum Response Element ◽  
Response Element ◽  
Endothelin 1 ◽  
Dependent Protein ◽  
Serum Response ◽  
Ca2 Channels

Endothelin-1 (ET-1) triggers poorly understood nuclear signaling cascades that control gene expression, cell growth, and differentiation. To better understand how ET-1 regulates gene expression, we asked whether voltage-insensitive Ca2+ channels and Ca2+/calmodulin-dependent protein kinases (CaMKs) propagate signals from ET-1 receptors to the c-fos promoter in mesangial cells. Ca2+ influx through voltage-insensitive Ca2+ channels, one of the earliest postreceptor events in ET-1 signaling, mediated induction of c-fos mRNA and activation of the c-fos promoter by ET-1. A CaMK inhibitor (KN-93) blocked activation of the c-fos promoter by ET-1. Ectopic expression of CaMKII potentiated stimulation by ET-1, providing further evidence that CaMKs contribute to c-fos promoter activation by ET-1. The c-fos serum response element was necessary but not sufficient for CaMKII to activate the c-fos promoter. Activation of the c-fos promoter by ET-1 and CaMKII also required the FAP cis element, an AP-1-like sequence adjacent to the serum response element. Thus, voltage-insensitive Ca2+ channels and CaMKs apparently propagate ET-1 signals to the c-fos promoter that require multiple, interdependent cis elements. Moreover, these experiments suggest an important role for voltage-insensitive Ca2+ channels in nuclear signal transduction in nonexcitable cells.

scholarly journals The Rho effector, PKN, regulates ANF gene transcription in cardiomyocytes through a serum response element

2000 ◽  
Vol 278 (6) ◽  
pp. H1769-H1774 ◽  
Author(s):  
Michael R. Morissette ◽  
Valerie P. Sah ◽  
Christopher C. Glembotski ◽  
Joan Heller Brown
Keyword(s):  
Gene Expression ◽  
Reporter Gene ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Common Element ◽  
Luciferase Reporter ◽  
Serum Response Element ◽  
Transcriptional Responses ◽  
Response Element ◽  
Serum Response

The low-molecular-weight GTP-binding protein RhoA mediates hypertrophic growth and atrial natriuretic factor (ANF) gene expression in neonatal rat ventricular myocytes. Neither the effector nor the promoter elements through which Rho exerts its regulatory effects on ANF gene expression have been elucidated. When constitutively activated forms of Rho kinase and two protein kinase C-related kinases, PKN (PRK1) and PRK2, were compared, only PKN generated a robust stimulation of a luciferase reporter gene driven by a 638-bp fragment on the ANF promoter. This ANF promoter fragment contains a proximal serum response element (SRE) and an Sp-1-like element required for the transcriptional response to phenylephrine (PE). This response was inhibited by dominant negative Rho. The ability of dominant negative Rho to inhibit the response to PE and the ability of PKN to stimulate ANF reporter gene expression were both lost when the SRE was mutated. Mutation of the Sp-1-like element also attenuated the response to PKN. A minimal promoter driven by ANF SRE sequences was sufficient to confer Rho- and PKN-mediated gene expression. Interestingly, PKN preferentially stimulated the ANF versus the c- fos SRE reporter gene. Thus PKN and Rho are able to regulate transcriptional activation of the ANF SRE by a common element that could implicate PKN as a downstream effector of Rho in transcriptional responses associated with hypertrophy.

scholarly journals Loss of serum response element-binding activity and hyperphosphorylation of serum response factor during cellular aging.

1994 ◽  
Vol 14 (7) ◽  
pp. 4991-4999 ◽  
Author(s):  
P W Atadja ◽  
K F Stringer ◽  
K T Riabowol
Keyword(s):  
Gene Expression ◽  
Serum Response Factor ◽  
Cellular Aging ◽  
Response Factor ◽  
Serum Response Element ◽  
Early Passage ◽  
Core Element ◽  
Response Element ◽  
Serum Response

Human diploid fibroblasts undergo a limited number of population doublings in vitro and are used widely as a model of cellular aging. Despite growing evidence that cellular aging occurs as a consequence of altered gene expression, little is known about the activity of transcription factors in aging cells. Here, we report a dramatic reduction in the ability of proteins extracted from the nuclei of near-senescent fibroblasts to bind the serum response element which is necessary for serum-induced transcription of the c-fos gene. In contrast, the activities of proteins binding to the RNA polymerase core element, TATA, as well as to the cyclic AMP response element were maintained during cellular aging. While no major differences in the expression of the serum response factor (SRF) that binds the serum response element were seen between early-passage and late-passage cells, hyperphosphorylation of SRF was observed in near-senescent cells. Furthermore, removal of phosphatase inhibitors during the isolation of endogenous nuclear proteins restored the ability of SRF isolated from old cells to bind the SRE. These data, therefore, indicate that hyperphosphorylation of SRF plays a role in altering the ability of this protein to bind to DNA and regulate gene expression in senescent cells.

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