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Articles by S Mahavadi
Total Records ( 7 ) for S Mahavadi
  W Hu , F Li , S Mahavadi and K. S. Murthy
 

Initial Ca2+-dependent contraction of intestinal smooth muscle is inhibited upon IL-1β treatment. The decrease in contraction reflects the upregulation of regulator of G protein signaling-4 (RGS4) via the canonical inhibitor of NF-B kinase-2 (IKK2)/IB-/NF-B pathway. Here, we show that the activation of various protein kinases, including ERK1/2, p38 MAPK, and phosphoinositide 3-kinase (PI3K), differentially modulates IL-1β-induced upregulation of RGS4 in rabbit colonic muscle cells. IL-1β treatment caused a transient phosphorylation of ERK1/2 and p38 MAPK. It also caused the phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β), sequential downstream effectors of PI3K. Pretreatment with PD-98059 (an ERK inhibitor) and SB-203580 (a p38 MAPK inhibitor) significantly inhibited IL-1β-induced RGS4 expression. In contrast, LY-294002 (a PI3K inhibitor) augmented, whereas GSK3β inhibitors inhibited, IL-1β-induced RGS4 expression. PD-98059 blocked IL-1β-induced phosphorylation of IKK2, degradation of IB-, and phosphorylation and nuclear translocation of NF-B subunit p65, whereas SB-203580 had a marginal effect, implying that the effect of ERK1/2 is exerted on the canonical IKK2/IB-/p65 pathway of NF-B activation but that the effect of p38 MAPK may not predominantly involve NF-B signaling. The increase in RGS4 expression enhanced by LY-294002 was accompanied by an increase in the phosphorylation of IKK2/IB-/p65 and blocked by pretreatment with inhibitors of IKK2 (IKK2-IV) and IB- (MG-132). Inhibition of GSK3β abolished IL-1β-induced phosphorylation of IKK2/p65. These findings suggest that ERK1/2 and p38 MAPK enhance IL-1β-induced upregulation of RGS4; the effect of ERK1/2 reflects its ability to promote IKK2 phosphorylation and increase NF-B activity. GSK3β acts normally to augment the activation of the canonical NF-B signaling. The PI3K/Akt/GSK3β pathway attenuates IL-1β-induced upregulation of RGS4 expression by inhibiting NF-B activation.

  F Li , D. Y Hu , S Liu , S Mahavadi , W Yen , K. S Murthy , K Khalili and W. Hu
 

Regulator of G protein signaling 4 (RGS4) regulates the strength and duration of G protein signaling and plays an important role in smooth muscle contraction, cardiac development, and psychiatric disorders. Little is known about the posttranscriptional regulation of RGS4 expression. We cloned the full-length cDNA of rabbit RGS4, which contains a long 3'-untranslated region (UTR) with several AU-rich elements (AREs). We determined whether RGS4 mRNA stability is mediated by the RNA-binding protein human antigen R (HuR) and contributes to IL-1β-induced upregulation of RGS4 expression. We show that IL-1β treatment in colonic smooth muscle cells doubled the half-life of RGS4 mRNA. Addition of RGS4 3'-UTR to the downstream of Renilla luciferase reporter induced dramatic reduction in the enzyme activity and mRNA expression of luciferase, which was attenuated by the site-directed mutation of the two 3'-most ARE sites. IL-1β increased luciferase mRNA stability in a UTR-dependent manner. Knockdown of HuR significantly aggravated UTR-mediated instability of luciferase and inhibited IL-1β-induced upregulation of RGS4 mRNA. In addition, IL-1β increased cytosolic translocation and RGS4 mRNA binding of HuR. These findings suggest that 3'-most ARE sites within RGS4 3'-UTR are essential for the instability of RGS4 mRNA and IL-1β promotes the stability of RGS4 mRNA through HuR.

 
 
 
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