scholarly journals A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition

2019 ◽  
Author(s):  
Jing Li ◽  
Go Urabe ◽  
Mengxue Zhang ◽  
Yitao Huang ◽  
Bowen Wang ◽  
...  
Keyword(s):  
Serum Response Factor ◽  
Fibroblast Cell ◽  
Cell Type ◽  
Centriole Duplication ◽  
Type Transition ◽  
Receptor Inhibition ◽  
Actin Expression ◽  
Adventitial Fibroblast ◽  
Serum Response

AbstractA divergent member of the polo-like kinase family, PLK4 is known for its canonical role in centriole duplication. Its non-canonical function and regulators are poorly defined. Here we investigated PLK4’s activation and expression and regulations thereof in rat adventitial fibroblast cell-type transition induced by platelet-derived growth factor (PDGF-AA).Experiments using siRNA and selective inhibitor (centrinone-B) revealed a role for PLK4 not only in AA-induced proliferation/migration, but also in serum response factor (SRF) activation and smooth muscle α-actin expression. PDGFR (receptor) inhibition abrogated AA-stimulated PLK4 activation (phosphorylation) and expression; P38 inhibition (siRNA, inhibitor) downstream of PDGFR also mitigated PLK4 activation. Furthermore, transcription of PLK4 (and PDGFRα) was repressed by pan-inhibition of the bromodomain/extraterminal family of chromatin-bookmark readers (BRD2, BRD3, BRD4), an effect determined herein as mainly mediated by BRD4. In vivo, periadventitial administration of centrinone-B reduced collagen content and thickness of the adventitia in a rat model of carotid artery injury.In summary, we have identified a non-canonical role for PLK4 in SRF activation and its regulations by BRD4/PDGFRα-dominated pathways. Results in this study suggest PLK4 inhibition as a potential anti-fibrotic intervention.

scholarly journals Myozap, a Novel Intercalated Disc Protein, Activates Serum Response Factor–Dependent Signaling and Is Required to Maintain Cardiac Function In Vivo

2010 ◽  
Vol 106 (5) ◽  
pp. 880-890 ◽  
Author(s):  
Thalia S. Seeger ◽  
Derk Frank ◽  
Claudia Rohr ◽  
Rainer Will ◽  
Steffen Just ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Serum Response Factor ◽  
Response Factor ◽  
Intercalated Disc ◽  
Serum Response

Functional antagonism between YY1 and the serum response factor

1992 ◽  
Vol 12 (9) ◽  
pp. 4209-4214
Author(s):  
A Gualberto ◽  
D LePage ◽  
G Pons ◽  
S L Mader ◽  
K Park ◽  
...  
Keyword(s):  
Serum Response Factor ◽  
Regulatory Element ◽  
Target Sequence ◽  
Response Factor ◽  
Basal Expression ◽  
Actin Promoter ◽  
Alpha Actin ◽  
Serum Response

The rapid, transient induction of the c-fos proto-oncogene by serum growth factors is mediated by the serum response element (SRE). The SRE shares homology with the muscle regulatory element (MRE) of the skeletal alpha-actin promoter. It is not known how these elements respond to proliferative and cell-type-specific signals, but the response appears to involve the binding of the serum response factor (SRF) and other proteins. Here, we report that YY1, a multifunctional transcription factor, binds to SRE and MRE sequences in vitro. The methylation interference footprint of YY1 overlaps with that of the SRF, and YY1 competes with the SRF for binding to these DNA elements. Overexpression of YY1 repressed serum-inducible and basal expression from the c-fos promoter and repressed basal expression from the skeletal alpha-actin promoter. YY1 also repressed expression from the individual SRE and MRE sequences upstream from a TATA element. Unlike that of YY1, SRF overexpression alone did not influence the transcriptional activity of the target sequence, but SRF overexpression could reverse YY1-mediated trans repression. These data suggest that YY1 and the SRF have antagonistic functions in vivo.

Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factor

2001 ◽  
Vol 280 (4) ◽  
pp. H1782-H1792 ◽  
Author(s):  
Xiaomin Zhang ◽  
Gohar Azhar ◽  
Jianyuan Chai ◽  
Pamela Sheridan ◽  
Koichiro Nagano ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Muscle ◽  
Serum Response Factor ◽  
Interstitial Fibrosis ◽  
Weight Ratio ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Response Factor ◽  
Serum Response

Serum response factor (SRF), a member of the MCM1, agamous, deficiens, SRF (MADS) family of transcriptional activators, has been implicated in the transcriptional control of a number of cardiac muscle genes, including cardiac α-actin, skeletal α-actin, α-myosin heavy chain (α-MHC), and β-MHC. To better understand the in vivo role of SRF in regulating genes responsible for maintenance of cardiac function, we sought to test the hypothesis that increased cardiac-specific SRF expression might be associated with altered cardiac morphology and function. We generated transgenic mice with cardiac-specific overexpression of the human SRF gene. The transgenic mice developed cardiomyopathy and exhibited increased heart weight-to-body weight ratio, increased heart weight, and four-chamber dilation. Histological examination revealed cardiomyocyte hypertrophy, collagen deposition, and interstitial fibrosis. SRF overexpression altered the expression of SRF-regulated genes and resulted in cardiac muscle dysfunction. Our results demonstrate that sustained overexpression of SRF, in the absence of other stimuli, is sufficient to induce cardiac change and suggest that SRF is likely to be one of the downstream effectors of the signaling pathways involved in mediating cardiac hypertrophy.

scholarly journals Novel Transcription Coactivator Complex Containing Activating Signal Cointegrator 1

2002 ◽  
Vol 22 (14) ◽  
pp. 5203-5211 ◽  
Author(s):  
Dong-Ju Jung ◽  
Hee-Sook Sung ◽  
Young-Wha Goo ◽  
Hyun Mi Lee ◽  
Ok Ku Park ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Serum Response Factor ◽  
Ectopic Expression ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Mutant Form ◽  
Negative Effects ◽  
Direct Binding ◽  
Serum Response

ABSTRACT Human activating signal cointegrator 1 (hASC-1) was originally isolated as a transcriptional coactivator of nuclear receptors. Here we report that ASC-1 exists as a steady-state complex associated with three polypeptides, P200, P100, and P50, in HeLa nuclei; stimulates transactivation by serum response factor (SRF), activating protein 1 (AP-1), and nuclear factor κB (NF-κB) through direct binding to SRF, c-Jun, p50, and p65; and relieves the previously described transrepression between nuclear receptors and either AP-1 or NF-κB. Interestingly, ectopic expression of Caenorhabditis elegans ASC-1 (ceASC-1), an ASC-1 homologue that binds P200 and P100, like hASC-1, while weakly interacting only with p65, in HeLa cells appears to replace endogenous hASC-1 from the hASC-1 complex and exerts potent dominant-negative effects on AP-1, NF-κB, and SRF transactivation. In addition, neutralization of endogenous P50 by single-cell microinjection of a P50 antibody inhibits AP-1 transactivation; the inhibition is relieved by coexpression of wild-type P50, but not of P50ΔKH, a mutant form that does not interact with P200. Overall, these results suggest that the endogenous hASC-1 complex appears to play an essential role in AP-1, SRF, and NF-κB transactivation and to mediate the transrepression between nuclear receptors and either AP-1 or NF-κB in vivo.

scholarly journals Cardiac Tissue Enriched Factors Serum Response Factor and GATA-4 Are Mutual Coregulators

2000 ◽  
Vol 20 (20) ◽  
pp. 7550-7558 ◽  
Author(s):  
Narasimhaswamy S. Belaguli ◽  
Jorge L. Sepulveda ◽  
Vishal Nigam ◽  
Frédéric Charron ◽  
Mona Nemer ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Cardiac Tissue ◽  
Serum Response Factor ◽  
Zinc Finger Protein ◽  
Response Factor ◽  
Mads Box ◽  
Cardiovascular Tissue ◽  
Serum Response

ABSTRACT Combinatorial interaction among cardiac tissue-restricted enriched transcription factors may facilitate the expression of cardiac tissue-restricted genes. Here we show that the MADS box factor serum response factor (SRF) cooperates with the zinc finger protein GATA-4 to synergistically activate numerous myogenic and nonmyogenic serum response element (SRE)-dependent promoters in CV1 fibroblasts. In the absence of GATA binding sites, synergistic activation depends on binding of SRF to the proximal CArG box sequence in the cardiac and skeletal α-actin promoter. GATA-4's C-terminal activation domain is obligatory for synergistic coactivation with SRF, and its N-terminal domain and first zinc finger are inhibitory. SRF and GATA-4 physically associate both in vivo and in vitro through their MADS box and the second zinc finger domains as determined by protein A pullout assays and by in vivo one-hybrid transfection assays using Gal4 fusion proteins. Other cardiovascular tissue-restricted GATA factors, such as GATA-5 and GATA-6, were equivalent to GATA-4 in coactivating SRE-dependent targets. Thus, interaction between the MADS box and C4 zinc finger proteins, a novel regulatory paradigm, mediates activation of SRF-dependent gene expression.

scholarly journals Cell-specific regulation of oncogene-responsive sequences of the c-fos promoter

1991 ◽  
Vol 11 (10) ◽  
pp. 5381-5387
Author(s):  
A Gutman ◽  
C Wasylyk ◽  
B Wasylyk
Keyword(s):  
Hela Cells ◽  
Serum Response Factor ◽  
Tumor Promoter ◽  
3T3 Cells ◽  
Carg Box ◽  
Specific Regulation ◽  
Nih 3T3 ◽  
Serum Response ◽  
Nih 3T3 Cells

We have identified oncogene-responsive sequences in the human c-fos promoter that mediate induction of transcription by several nonnuclear oncoproteins and the tumor promoter TPA. These sequences are regulated in a cell-specific manner. (i) In NIH 3T3 cells, the CArG box of the c-fos promoter is sufficient to mediate activation by oncogenes. (ii) In contrast, in HeLa cells, additional flanking sequences are also required, including the outer arm of the serum response element and the FAP site. We also show that the serum response factor, which binds to the CArG box, activates transcription in vivo in NIH 3T3 cells but not in HeLa cells. Finally, we present evidence that the intracellular level of the c-Fos protein could be a major determinant of cell-specific regulation of these oncogene-responsive elements of the c-fos promoter.

scholarly journals Delayed liver regeneration in mice lacking liver serum response factor

2007 ◽  
Vol 292 (4) ◽  
pp. G996-G1001 ◽  
Author(s):  
M. Ujue Latasa ◽  
Dominique Couton ◽  
Claude Charvet ◽  
Aurélie Lafanechère ◽  
Jacques-Emmanuel Guidotti ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Serum Response Factor ◽  
Early Response ◽  
Mutant Mice ◽  
Response Factor ◽  
Impaired Liver ◽  
Serum Response

Various immediate early genes (IEGs) upregulated during the early process of liver regeneration are transcriptional targets of the serum response factor (SRF). We show here that the expression of SRF is rapidly induced in rodent liver after partial hepatectomy. Because the inactivation of the SRF gene in mice is embryonic lethal, the in vivo role of SRF in liver regeneration after partial hepatectomy was analyzed in mutant mice conditionally deleted for SRF in the liver. We demonstrate that SRF is not an essential factor for liver ontogenesis. However, adult mutant mice show impaired liver regeneration after partial hepatectomy, associated with a blunted upregulation of various SRF target IEGs. In conclusion, our work suggests that SRF is an early response transcription factor that may contribute to the initial phases of liver regeneration through its activation of IEGs.

scholarly journals Cell-specific regulation of oncogene-responsive sequences of the c-fos promoter.

1991 ◽  
Vol 11 (10) ◽  
pp. 5381-5387 ◽  
Author(s):  
A Gutman ◽  
C Wasylyk ◽  
B Wasylyk
Keyword(s):  
Hela Cells ◽  
Serum Response Factor ◽  
Tumor Promoter ◽  
3T3 Cells ◽  
Carg Box ◽  
Specific Regulation ◽  
Nih 3T3 ◽  
Serum Response ◽  
Nih 3T3 Cells

We have identified oncogene-responsive sequences in the human c-fos promoter that mediate induction of transcription by several nonnuclear oncoproteins and the tumor promoter TPA. These sequences are regulated in a cell-specific manner. (i) In NIH 3T3 cells, the CArG box of the c-fos promoter is sufficient to mediate activation by oncogenes. (ii) In contrast, in HeLa cells, additional flanking sequences are also required, including the outer arm of the serum response element and the FAP site. We also show that the serum response factor, which binds to the CArG box, activates transcription in vivo in NIH 3T3 cells but not in HeLa cells. Finally, we present evidence that the intracellular level of the c-Fos protein could be a major determinant of cell-specific regulation of these oncogene-responsive elements of the c-fos promoter.

scholarly journals Functional antagonism between YY1 and the serum response factor.

1992 ◽  
Vol 12 (9) ◽  
pp. 4209-4214 ◽  
Author(s):  
A Gualberto ◽  
D LePage ◽  
G Pons ◽  
S L Mader ◽  
K Park ◽  
...  
Keyword(s):  
Serum Response Factor ◽  
Regulatory Element ◽  
Target Sequence ◽  
Response Factor ◽  
Basal Expression ◽  
Actin Promoter ◽  
Alpha Actin ◽  
Serum Response

The rapid, transient induction of the c-fos proto-oncogene by serum growth factors is mediated by the serum response element (SRE). The SRE shares homology with the muscle regulatory element (MRE) of the skeletal alpha-actin promoter. It is not known how these elements respond to proliferative and cell-type-specific signals, but the response appears to involve the binding of the serum response factor (SRF) and other proteins. Here, we report that YY1, a multifunctional transcription factor, binds to SRE and MRE sequences in vitro. The methylation interference footprint of YY1 overlaps with that of the SRF, and YY1 competes with the SRF for binding to these DNA elements. Overexpression of YY1 repressed serum-inducible and basal expression from the c-fos promoter and repressed basal expression from the skeletal alpha-actin promoter. YY1 also repressed expression from the individual SRE and MRE sequences upstream from a TATA element. Unlike that of YY1, SRF overexpression alone did not influence the transcriptional activity of the target sequence, but SRF overexpression could reverse YY1-mediated trans repression. These data suggest that YY1 and the SRF have antagonistic functions in vivo.

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