Patterns of Gene Expression Differentially Regulated by Platelet-derived Growth Factor and Hypertrophic Stimuli in Vascular Smooth Muscle Cells

Kaplan-Albuquerque, Nihal; Bogaert, Yolanda E.; Putten, Vicki Van; Weiser‐Evans, Mary C.M.; Nemenoff, Raphael A.

doi:10.1074/jbc.m500917200

Cited by 42 publications

(36 citation statements)

References 45 publications

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“…Based on the gene array analysis, 30 PDGF-BB increased the mRNA expression of a condroidin sulfate proteoglycan, Versican, and a cytokine, Gro, but decreased the expression of Collagen X 1␣. Quantitative Real-Time PCR (Q-RT-PCR) analysis showed that VSMC depleted of SRF (SRF shRNAi Clones #2, and #6) also had marked increases in mRNA levels for Versican when compared with control cells (U6.1/ Neo clones #1 and #2).…”

Section: Resultsmentioning

confidence: 99%

Depletion of Serum Response Factor by RNA Interference Mimics the Mitogenic Effects of Platelet Derived Growth Factor-BB in Vascular Smooth Muscle Cells

Kaplan-Albuquerque

Putten

Weiser‐Evans

et al. 2005

Circulation Research

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Abstract-Promoters of many smooth muscle-specific genes (SM-genes) contain multiple CArG boxes, which represent a binding site for serum response factor (SRF). Transciptional control through these regions involves interactions with SRF and specific coactivators such as myocardin. We have previously reported that suppression of SM-gene expression by platelet derived growth factor (PDGF) is associated with redistribution of SRF, leading to lower intra-nuclear levels, and a reduction in SRF transactivation. To further assess the role of SRF depletion on VSMC phenotype, the current study used RNA interference (RNAi). Two SRF-specific sequences constructed as hairpins were stably expressed in rat VSMC. Clones expressing SRF RNAi had no detectable SRF expression by immunoblotting, and showed diminished levels of SM ␣-actin protein and promoter activity. Unexpectedly, depletion of VSMC resulted in increased rates of proliferation and migration. Several genes whose expression is increased by PDGF stimulation, including c-Jun, were similarly induced in cells lacking SRF. Key Words: vascular smooth muscle cells Ⅲ serum response factor Ⅲ RNA interference Ⅲ platelet derived growth factor P henotypic modulation of vascular smooth muscle cells (VSMC 1 ) is critical during development and in the onset of diseases such as atherosclerosis and hypertension. Atherosclerosis is a leading cause of heart disease and stroke and causes Ϸ50% of all deaths. 2,3 Therefore, understanding the physiology of large vessels will help to identify the cause of a primary cardiovascular disease. VSMC in mature animals express multiple contractile proteins to maintain vascular tone. These proteins are markers for the differentiated contractile phenotype. Unlike myocardial and skeletal muscle cells, VSMC are highly plastic and retain the ability to modulate their phenotype. 4 -6 Environmental factors can alter the expression levels of these contractile proteins, leading to a switch from a differentiated phenotype, characterized by high expression, to a proliferative, dedifferentiated phenotype characterized by low expression. This occurs in pathophysiologic states of large arteries such as atherosclerosis, where migration and proliferation of neointimal VSMC lead to vascular remodeling. 7,8 In adult cultured VSMC, vasoconstrictors, such as angiotensin II or arginine vasopressin (AVP), increase expression of smooth muscle (SM) markers such as SMA and SM22␣, whereas growth factors such as platelet derived growth factor (PDGF) decrease protein and mRNA levels of these proteins. 1,9 -11 We have shown that these effects are mediated through transcriptional regulation of SM specific promoter activity, and have defined specific signal transduction pathways that regulate SM specific gene expression by AVP or PDGF. AVP-induced increases in gene expression require c-jun amino terminal kinase and p38 MAP kinases, whereas PDGF-induced suppression is mediated by Ras, and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. 1,[11][12][13] The promoters of these SM...

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Section: Resultsmentioning

confidence: 99%

Depletion of Serum Response Factor by RNA Interference Mimics the Mitogenic Effects of Platelet Derived Growth Factor-BB in Vascular Smooth Muscle Cells

Kaplan-Albuquerque

Putten

Weiser‐Evans

et al. 2005

Circulation Research

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“…During injury to blood vessels, PDGF triggers phenotypic modulation, which is mediated by changes in patterns of gene expression. Recently, a subset of genes has been defined that are up-or down-regulated in VSMC by PDGF (Kaplan-Albuquerque et al 2005).…”

Section: Introductionmentioning

confidence: 99%

A proteomic approach to the investigation of early events involved in vascular smooth muscle cell activation

et al. 2007

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Vascular smooth muscle cells (VSMC) are mature cells that maintain great plasticity. This distinctive feature is the basis of the VSMC migration and proliferation involved in cardiovascular diseases. We have used a proteomic approach to the molecular changes that promote the switch of VSMC from having a quiescent to activatedproliferating phenotype. In particular, we have focused on modulations occurring during tyrosine-phosphorylation following cell activation by serum or single growth factors, such as insulin-like growth factor 1 or platelet-derived growth factor. A comparison of two-dimensional polyacrylamide gel profiles from quiescent or activated-proliferating VSMC has allowed us to recognize a number of differences in protein expression. Several differentially expressed proteins have been identified by mass spectrometry, and their time-course changes during tyrosine-phosphorylation have been documented from time zero till 48 h after stimulation. We have documented a general decrease of the tyrosine-phosphorylation level within the first few minutes after stimulation followed by a recovery that is quick and dramatic for some chaperones and redox enzymes but not so significant for enzymes of glucose metabolism. With regard to cytoskeleton components, no remarkable fluctuations have been detected at the earliest time points, except for those relative to α-actin, which displays an impressive decrease. A comparison of the early stages of cell stimulation after the administration of serum or single growth factors has brought to light important differences in the phosphorylation of chaperones, thereby suggesting their crucial role in VSMC activation.

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“…The induction of PDGFB mRNA and the expression of many of its first degree interacting nodes, is consistent with PDGFB signaling being upregulated by NKX3.1. For example, three nodes that were upregulated by NKX3.1 (CRYAB, SERPINA3, CDKN1A) and two nodes that were downregulated (DAB2, TAGLN) were previously shown to be controlled by PDGFB in the same manner ( Supplementary Figure S4; 80, 81 ). PDGFB is also known to activate PPAR/RXRα-dependent transcription.…”

Section: Resultsmentioning

confidence: 96%

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

Yang

Chung²,

et al. 2014

F1000Res

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NKX3.1 is a homeobox transcription factor whose function as a prostate tumor suppressor remains insufficiently understood because neither the transcriptional program governed by NKX3.1, nor its interacting proteins have been fully revealed. Using affinity purification and mass spectrometry, we have established an extensive NKX3.1 interactome which contains the DNA repair proteins Ku70, Ku80, and PARP, thus providing a molecular underpinning to previous reports implicating NKX3.1 in DNA repair. Transcriptomic profiling of NKX3.1-negative prostate epithelial cells acutely expressing NKX3.1 revealed a rapid and complex response that is a near mirror image of the gene expression signature of human prostatic intraepithelial neoplasia (PIN). Pathway and network analyses suggested that NKX3.1 actuates a cellular reprogramming toward luminal cell differentiation characterized by suppression of pro-oncogenic c-MYC and interferon-STAT signaling and activation of tumor suppressor pathways. Consistently, ectopic expression of NKX3.1 conferred a growth arrest depending on TNFα and JNK signaling. We propose that the tumor suppressor function of NKX3.1 entails a transcriptional program that maintains the differentiation state of secretory luminal cells and that disruption of NKX3.1 contributes to prostate tumorigenesis by permitting luminal cell de-differentiation potentially augmented by defects in DNA repair.

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Patterns of Gene Expression Differentially Regulated by Platelet-derived Growth Factor and Hypertrophic Stimuli in Vascular Smooth Muscle Cells

Cited by 42 publications

References 45 publications

Depletion of Serum Response Factor by RNA Interference Mimics the Mitogenic Effects of Platelet Derived Growth Factor-BB in Vascular Smooth Muscle Cells

Depletion of Serum Response Factor by RNA Interference Mimics the Mitogenic Effects of Platelet Derived Growth Factor-BB in Vascular Smooth Muscle Cells

A proteomic approach to the investigation of early events involved in vascular smooth muscle cell activation

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

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