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.

scholarly journals A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity.

1993 ◽  
Vol 13 (10) ◽  
pp. 6260-6273 ◽  
Author(s):  
V M Rivera ◽  
C K Miranti ◽  
R P Misra ◽  
D D Ginty ◽  
R H Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Serum Response Factor ◽  
Critical Role ◽  
Response Factor ◽  
Serum Response Element ◽  
Response Element ◽  
Ribosomal S6 Kinase ◽  
Serum Response

A signaling pathway by which growth factors may induce transcription of the c-fos proto-oncogene has been characterized. Growth factor stimulation of quiescent fibroblasts activates a protein kinase cascade that leads to the rapid and transient phosphorylation of the serum response factor (SRF), a regulator of c-fos transcription. The in vivo kinetics of SRF phosphorylation and dephosphorylation parallel the activation and subsequent repression of c-fos transcription, suggesting that this phosphorylation event plays a critical role in the control of c-fos expression. The ribosomal S6 kinase pp90rsk, a growth factor-inducible kinase, phosphorylates SRF in vitro at serine 103, the site that becomes newly phosphorylated upon growth factor stimulation in vivo. Phosphorylation of serine 103 significantly enhances the affinity and rate with which SRF associates with its binding site, the serum response element, within the c-fos promoter. These results suggest a model in which the growth factor-induced phosphorylation of SRF at serine 103 contributes to the activation of c-fos transcription by facilitating the formation of an active transcription complex at the serum response element.

A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity

1993 ◽  
Vol 13 (10) ◽  
pp. 6260-6273
Author(s):  
V M Rivera ◽  
C K Miranti ◽  
R P Misra ◽  
D D Ginty ◽  
R H Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Serum Response Factor ◽  
Critical Role ◽  
Response Factor ◽  
Serum Response Element ◽  
Response Element ◽  
Ribosomal S6 Kinase ◽  
Serum Response

A signaling pathway by which growth factors may induce transcription of the c-fos proto-oncogene has been characterized. Growth factor stimulation of quiescent fibroblasts activates a protein kinase cascade that leads to the rapid and transient phosphorylation of the serum response factor (SRF), a regulator of c-fos transcription. The in vivo kinetics of SRF phosphorylation and dephosphorylation parallel the activation and subsequent repression of c-fos transcription, suggesting that this phosphorylation event plays a critical role in the control of c-fos expression. The ribosomal S6 kinase pp90rsk, a growth factor-inducible kinase, phosphorylates SRF in vitro at serine 103, the site that becomes newly phosphorylated upon growth factor stimulation in vivo. Phosphorylation of serine 103 significantly enhances the affinity and rate with which SRF associates with its binding site, the serum response element, within the c-fos promoter. These results suggest a model in which the growth factor-induced phosphorylation of SRF at serine 103 contributes to the activation of c-fos transcription by facilitating the formation of an active transcription complex at the serum response element.

scholarly journals The serum response factor is extensively modified by phosphorylation following its synthesis in serum-stimulated fibroblasts.

1991 ◽  
Vol 11 (9) ◽  
pp. 4545-4554 ◽  
Author(s):  
R P Misra ◽  
V M Rivera ◽  
J M Wang ◽  
P D Fan ◽  
M E Greenberg
Keyword(s):  
Inner Core ◽  
Serum Response Factor ◽  
Transcriptional Response ◽  
Biochemical Properties ◽  
Transcriptional Level ◽  
Response Factor ◽  
Serum Response Element ◽  
Response Element ◽  
Serum Stimulation ◽  
Serum Response

Growth factor regulation of c-fos proto-oncogene transcription is mediated by a 20-bp region of dyad symmetry, termed the serum response element. The inner core of this element binds a 67-kDa phosphoprotein, the serum response factor (SRF), that is thought to play a pivotal role in the c-fos transcriptional response. To investigate the mechanism by which SRF regulates c-fos expression, we generated polyclonal anti-SRF antibodies and used these antibodies to analyze the biochemical properties of SRF. These studies indicate that the synthesis of SRF is transient, occurring within 30 min to 4 h after serum stimulation of quiescent fibroblasts. Newly synthesized SRF is transported to the nucleus, where it is increasingly modified by phosphorylation during progression through the cell cycle. Within 2 h of serum stimulation, differentially modified forms of SRF can be distinguished on the basis of the ability to bind a synthetic serum response element. SRF protein exhibits a half-life of greater than 12 h and is predominantly nuclear, with no change occurring in its localization upon serum stimulation. We find that the induction of SRF synthesis is regulated at the transcriptional level and that cytoplasmic SRF mRNA is transiently expressed with somewhat delayed kinetics compared with c-fos mRNA expression. These features of SRF expression suggest a model whereby newly synthesized SRF functions in the shutoff of c-fos transcription.

Structural and dynamic changes of the serum response element and the core domain of serum response factor induced by their association

2010 ◽  
Vol 391 (1) ◽  
pp. 203-208 ◽  
Author(s):  
Josef Štěpánek ◽  
Vladimír Kopecký ◽  
Alberto Mezzetti ◽  
Pierre-Yves Turpin ◽  
Denise Paulin ◽  
...  
Keyword(s):  
Serum Response Factor ◽  
Response Factor ◽  
Serum Response Element ◽  
Dynamic Changes ◽  
Response Element ◽  
Core Domain ◽  
The Core ◽  
Serum Response

scholarly journals YY1 facilitates the association of serum response factor with the c-fos serum response element.

1995 ◽  
Vol 15 (11) ◽  
pp. 5975-5982 ◽  
Author(s):  
S Natesan ◽  
M Gilman
Keyword(s):  
Protein Interactions ◽  
Structural Changes ◽  
Serum Response Factor ◽  
Response Factor ◽  
Protein Protein Interactions ◽  
Serum Response Element ◽  
Response Element ◽  
General Role ◽  
A Site ◽  
Serum Response

YY1 is a multifunctional transcription factor that acts as an activator or repressor in different contexts. YY1 binds to multiple sites in the mouse c-fos promoter, inducing at each site a sharp DNA bend. Binding of YY1 to a site situated between the cyclic AMP response element (CRE) and the TATA box bends the DNA in a way that interferes with the interaction of proteins bound at the CRE and TATA elements, resulting in repression of transcription. Here, we show that binding of YY1 to a different site in the c-fos promoter has a different result. Binding of YY1 to the c-fos serum response element (SRE) enhances the binding of serum response factor (SRF). This enhancement requires the binding of YY1 to SRE DNA. YY1 and SRF can cooccupy the SRE at least transiently. In the region of overlapping contact, YY1 contacts DNA in the major groove, while SRF contacts DNA in the minor groove. YY1 also enhances the association of SRF with the SRE in transfected insect cells. Thus, although YY1 induces similar structural changes in DNA at different binding sites, it can have distinct local effects on protein-DNA and protein-protein interactions. These data support a general role for YY1 in the building of highly organized promoter complexes.

scholarly journals Mechanism of binding of serum response factor to serum response element

FEBS Journal ◽  
2005 ◽  
Vol 272 (12) ◽  
pp. 3105-3119 ◽  
Author(s):  
Alexis Huet ◽  
Ara Parlakian ◽  
Marie-Claire Arnaud ◽  
Jean-Marie Glandières ◽  
Pierre Valat ◽  
...  
Keyword(s):  
Serum Response Factor ◽  
Response Factor ◽  
Serum Response Element ◽  
Response Element ◽  
Serum Response

scholarly journals Neurokinin B Induces c-fos Transcription via Protein Kinase C and Activation of Serum Response Factor and Elk-1 in Immortalized GnRH Neurons

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3909-3919 ◽  
Author(s):  
Christine A. Glidewell-Kenney ◽  
Crystal Trang ◽  
Paul P. Shao ◽  
Navarre Gutierrez-Reed ◽  
Adaku M. Uzo-Okereke ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Serum Response Factor ◽  
Response Factor ◽  
Gnrh Neuron ◽  
Serum Response Element ◽  
Neurokinin B ◽  
Response Element ◽  
Kinase C ◽  
Serum Response

Abstract Mutations in neurokinin B (NKB) and its receptor, NK3R, were identified in human patients with hypogonadotropic hypogonadism, a disorder characterized by lack of puberty and infertility. Further studies have suggested that NKB acts at the level of the hypothalamus to control GnRH neuron activity, either directly or indirectly. We recently reported that treatment with senktide, a NK3R agonist, induced GnRH secretion and expression of c-fos mRNA in GT1-7 cells. Here, we map the responsive region in the murine c-fos promoter to between −400 and −200 bp, identify the signal transducer and activator of transcription (STAT) (−345) and serum response element (−310) sites as required for induction, a modulatory role for the Ets site (−318), and show that induction is protein kinase C dependent. Using gel shift and Gal4 assays, we further show that phosphorylation of Elk-1 leads to binding to DNA in complex with serum response factor at serum response element and Ets sites within the c-fos promoter. Thus, we determine molecular mechanisms involved in NKB regulation of c-fos induction, which may play a role in modulation of GnRH neuron activation.

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