A Novel Mechanism Involving Coordinated Regulation of Nuclear Levels and Acetylation of NF-YA and Bcl6 Activates RGS4 Transcription

Yang, Jianqi; Huang, Jie; Chatterjee, Tapan K.; Twait, Erik; Fisher, Rory A.

doi:10.1074/jbc.m110.121459

Cited by 11 publications

(14 citation statements)

References 52 publications

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“…However, the regulatory mechanism of Rgs4 expression has not been well understood. We and others have demonstrated that Rgs4 expression is transcriptionally regulated [6], [38], [64]–[67]. We have cloned and characterized the promoter region of rabbit Rgs4 [38].…”

Section: Discussionmentioning

confidence: 98%

MEKK1-MKK4-JNK-AP1 Pathway Negatively Regulates Rgs4 Expression in Colonic Smooth Muscle Cells

Zhang

Liu

et al. 2012

PLoS ONE

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Background Regulator of G-protein Signaling 4 (RGS4) plays an important role in regulating smooth muscle contraction, cardiac development, neural plasticity and psychiatric disorder. However, the underlying regulatory mechanisms remain elusive. Our recent studies have shown that upregulation of Rgs4 by interleukin (IL)-1β is mediated by the activation of NFκB signaling and modulated by extracellular signal-regulated kinases, p38 mitogen-activated protein kinase, and phosphoinositide-3 kinase. Here we investigate the effect of the c-Jun N-terminal kinase (JNK) pathway on Rgs4 expression in rabbit colonic smooth muscle cells.Methodology/Principal FindingsCultured cells at first passage were treated with or without IL-1β (10 ng/ml) in the presence or absence of the selective JNK inhibitor (SP600125) or JNK small hairpin RNA (shRNA). The expression levels of Rgs4 mRNA and protein were determined by real-time RT-PCR and Western blot respectively. SP600125 or JNK shRNA increased Rgs4 expression in the absence or presence of IL-1β stimulation. Overexpression of MEKK1, the key upstream kinase of JNK, inhibited Rgs4 expression, which was reversed by co-expression of JNK shRNA or dominant-negative mutants for MKK4 or JNK. Both constitutive and inducible upregulation of Rgs4 expression by SP600125 was significantly inhibited by pretreatment with the transcription inhibitor, actinomycin D. Dual reporter assay showed that pretreatment with SP600125 sensitized the promoter activity of Rgs4 in response to IL-1β. Mutation of the AP1-binding site within Rgs4 promoter increased the promoter activity. Western blot analysis confirmed that IL-1β treatment increased the phosphorylation of JNK, ATF-2 and c-Jun. Gel shift and chromatin immunoprecipitation assays validated that IL-1β increased the in vitro and ex vivo binding activities of AP1 within rabbit Rgs4 promoter.Conclusion/SignificanceActivation of MEKK1-MKK4-JNK-AP1 signal pathway plays a tonic inhibitory role in regulating Rgs4 transcription in rabbit colonic smooth muscle cells. This negative regulation may aid in maintaining the transient level of RGS4 expression.

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Section: Discussionmentioning

confidence: 98%

MEKK1-MKK4-JNK-AP1 Pathway Negatively Regulates Rgs4 Expression in Colonic Smooth Muscle Cells

Zhang

Liu

et al. 2012

PLoS ONE

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“…Our data provide information regarding a previously unknown molecular mechanism in which RGS4 promotes NSCLC cell proliferation by regulating miR-16 expression. The expression of miR-16 is downregulated in NSCLC tissue samples and cell lines as well as in other malignancies 35,37,40–50. In NSCLC, miR-16 suppresses tumor development by inhibiting cell proliferation and promoting apoptosis 29,41.…”

Section: Discussionmentioning

confidence: 99%

<p>RGS4 Regulates Proliferation And Apoptosis Of NSCLC Cells Via microRNA-16 And Brain-Derived Neurotrophic Factor</p>

He¹,

Yu²,

Luo³

et al. 2019

OTT

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PurposeRegulator of G-protein signaling (RGS) proteins are GTPase-activating proteins that target the α-subunit of heterotrimeric G proteins. Many studies have shown that RGS proteins contribute to tumorigenesis and metastasis. However, the mechanism in which RGS proteins, especially RGS4, affect the development of non-small cell lung cancer (NSCLC) remains unclear. The aim of this study was to characterize the role of RGS4 in NSCLC.MethodsRGS4 expression in NSCLC tissues was assessed using an immunohistochemistry tissue microarray. Additionally, RGS4 was knocked down using short-hairpin RNA to assess the regulatory function of RGS4 in the biological behaviors of human NSCLC cell lines. A xenograft lung cancer model in nude BALB/c mice was established to study whether RGS4 knockdown inhibits cancer cell proliferation in vivo.ResultsWe observed an increase in RGS4 protein levels in NSCLC samples. RGS4 knockdown inhibited cell proliferation and induced apoptosis in H1299 and PC9 cell lines, but did not affect cell migration. Moreover, we found that RGS4 negatively regulated the expression of microRNA-16 (miR-16), a tumor suppressor. The inhibition of miR-16 resulted in upregulated RGS4 expression. We also found that RGS4 regulated the expression of brain-derived neurotrophic factor (BDNF) and activated the BDNF-tropomyosin receptor kinase B signaling pathway.ConclusionThis study revealed that RGS4 overexpression positively correlated with the development of NSCLC. TDownstream RGS4 targets (eg, miR-16 and BDNF) might be involved in the development of NSCLC and may serve as potential therapeutic targets for its treatment.

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“…This gene has also been reported to control neurogenesis (Tiberi et al, 2012). Interestingly, BCL6 binds to the promoter of RGS4 to repress its transcription (Yang et al, 2010). RGS4 is a candidate vulnerability gene that was found to be down-regulated in previous studies in SCZ (Bowden et al, 2007;Erdely et al, 2006;Levitt et al, 2006;Mirnics et al, 2001).…”

Section: Idmentioning

confidence: 93%

CX3CR1 is dysregulated in blood and brain from schizophrenia patients

Bergon

Belzeaux

Comte

et al. 2015

Schizophrenia Research

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The molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory processes driven by diverse environmental factors play a significant role in its development. With gene expression studies having been conducted across a variety of sample types, e.g., blood and postmortem brain, it is possible to investigate convergent signatures that may reveal interactions between the immune and nervous systems in schizophrenia pathophysiology. We conducted two meta-analyses of schizophrenia microarray gene expression data (N=474) and non-psychiatric control (N=485) data from postmortem brain and blood. Then, we assessed whether significantly dysregulated genes in schizophrenia could be shared between blood and brain. To validate our findings, we selected a top gene candidate and analyzed its expression by RT-qPCR in a cohort of schizophrenia subjects stabilized by atypical antipsychotic monotherapy (N=29) and matched controls (N=31). Meta-analyses highlighted inflammation as the major biological process associated with schizophrenia and that the chemokine receptor CX3CR1 was significantly down-regulated in schizophrenia. This differential expression was also confirmed in our validation cohort. Given both the recent data demonstrating selective CX3CR1 expression in subsets of neuroimmune cells, as well as behavioral and neuropathological observations of CX3CR1 deficiency in mouse models, our results of reduced CX3CR1 expression adds further support for a role played by monocyte/microglia in the neurodevelopment of schizophrenia.

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A Novel Mechanism Involving Coordinated Regulation of Nuclear Levels and Acetylation of NF-YA and Bcl6 Activates RGS4 Transcription

Cited by 11 publications

References 52 publications

MEKK1-MKK4-JNK-AP1 Pathway Negatively Regulates Rgs4 Expression in Colonic Smooth Muscle Cells

MEKK1-MKK4-JNK-AP1 Pathway Negatively Regulates Rgs4 Expression in Colonic Smooth Muscle Cells

<p>RGS4 Regulates Proliferation And Apoptosis Of NSCLC Cells Via microRNA-16 And Brain-Derived Neurotrophic Factor</p>

CX3CR1 is dysregulated in blood and brain from schizophrenia patients

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