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R Sirianni, R Sirianni, BR Carr, V Pezzi and WE Rainey

Adrenal aldosterone synthesis is influenced by a variety of factors. The major physiological regulators of aldosterone production are angiotensin II (Ang IotaIota) and potassium (K(+)). Ang IotaIota stimulates aldosterone production through the activation of multiple intracellular signaling pathways. It has recently been demonstrated that Ang IotaIota activates src tyrosine kinases in vascular smooth muscle cells. The src family of tyrosine kinases are widely distributed non-receptor kinases that influence several signal transduction pathways. In the present study we evaluated the effect of a selective src family inhibitor, PP2, on aldosterone production using a human adrenocortical carcinoma-derived (H295R) cell line. Treatments for 6 or 48 h with PP2 (0.3 microM-10 microM) inhibited basal, Ang IotaIota, K(+) and dibutyryladenosine cyclic monophosphate (dbcAMP) stimulation of aldosterone production in a concentration-dependent manner. PP2 did not affect cell viability at any of the concentrations tested. Moreover, time course studies using PP2 (10 microM) for 6, 12, 24, and 48 h revealed a time-dependent inhibition of aldosterone production. Inhibition by PP2 (0.3-10 microM) was also observed for the metabolism of 22R-hydroxycholesterol (22R-OHChol) to aldosterone in H295R cells. Since 22R-OHChol is a substrate for cytochrome P450 side-chain cleavage enzyme (CYP11A) that does not require steroidogenic acute regulatory (StAR) protein for transport to the inner mitochondrial membrane, these results suggest that PP2 inhibition occurred beyond the rate-limiting step in aldosterone synthesis. Genistein, a non-specific tyrosine kinase inhibitor also blocked aldosterone production, but the inhibition was the result of a non-specific effect on 3beta-hydroxysteroid dehydrogenase (3betaHSD). In contrast, PP2 did not appear to act as a direct inhibitor of 3betaHSD activity. To further investigate the site of PP2 action, we examined its effect on H295R cell metabolism of [(14)C]progesterone using thin layer chromatography. PP2 treatment for 48 h caused an increase in the conversion of progesterone to 17alpha-hydroxyprogesterone. To determine if this apparent increase in 17alpha-hydroxylase activity was due to increased transcript, we examined the effect of PP2 on CYP17 mRNA. PP2 treatment caused an increase in CYP17 mRNA without an effect on 3betaHSD mRNA levels. Inhibition of protein synthesis with cycloheximide increased basal levels of CYP17 mRNA levels and blocked the induction observed by PP2. This suggests that new protein synthesis is a necessary part of PP2 induction of CYP17. Taken together these data suggest that the src tyrosine kinase inhibitor, PP2, is a potent inhibitor of aldosterone production. One mechanism for the inhibition is through an induction of CYP17 mRNA and enzyme activity. Src tyrosine kinases, therefore, may be involved with the promotion of a glomerulosa phenotype through the inhibition of CYP17 expression.

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Kenneth Siddle

-GlcNAc following insulin stimulation, and this in turn modulates their serine phosphorylation and attenuates insulin signal transduction ( Yang et al . 2008 ). IRS1 is O -GlcNAcylated at multiple sites in close proximity to SH2 domain-binding motifs

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S Bauersachs, S E Ulbrich, K Gross, S E M Schmidt, H H D Meyer, R Einspanier, H Wenigerkind, M Vermehren, H Blum, F Sinowatz and E Wolf

B. taurus decorin DCN NM_173906 1.9 2 21 Signal transduction, ECM remodelling B. taurus mRNA for similar to elongation

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Yan-ping Xu, Jia-jun Zhu, Fen Cheng, Ke-wen Jiang, Wei-zhong Gu, Zheng Shen, Yi-dong Wu, Li Liang and Li-zhong Du

and NO-enhanced growth and tube formation was observed in PPHN PAECs ( Gien et al . 2007 ). There is increasing evidence that ghrelin has a potent vasodilator effect. We hypothesize that ghrelin would prevent PPHN by altering signal transduction

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Young Ho Suh, Younyoung Kim, Jeong Hyun Bang, Kyoung Suk Choi, June Woo Lee, Won-Ho Kim, Tae Jeong Oh, Sungwhan An and Myeong Ho Jung

adipocyte in PI3-kinase dependent or independent signal transduction pathways ( Imamura et al. 1999 ). Therefore, the upregulation of RGS in insulin sensitive tissues could attenuate insulin stimulated GLUT4 translocation by inhibiting signaling by GTP

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Caroline M Gorvin

domain (ICD). Ionised calcium binds between the two lobes of the VFTD. In the presence of high calcium, the CASR is activated, leading to changes in its signal transduction and reduced PTH secretion. The CASR is a 1078-amino acid protein that

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Davide Calebiro, Viacheslav O Nikolaev and Martin J Lohse

Zerial M 2004 Not just a sink: endosomes in control of signal transduction . Current Opinion in Cell Biology 16 400 – 406 . Müllershausen F Zecri F Cetin C Billich A Guerini D Seuwen K 2009 Persistent signaling induced by FTY720

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Xiaodong Li, Stephanie L Nott, Yanfang Huang, Russell Hilf, Robert A Bambara, Xing Qiu, Andrei Yakovlev, Stephen Welle and Mesut Muyan

level of transcription of immediate/early estrogen responsive genes ( Frasor et al . 2003 ). Expression profiling revealed that the genes regulated by ERβ and ERβ EBD are involved in a broad range of function including metabolism, signal transduction

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Nima Sharifi, Robert J Lechleider and William L Farrar

( Massague et al . 2005 ). The antagonistic property of inhibin has to do with inhibin binding the type II activin receptor and TGFβRIII, forming a complex that interferes with activin binding the type II receptor, thereby inhibiting signal transduction

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Magdalena I Suszko and Teresa K Woodruff

follistatin and inhibin. Interestingly, both activin and inhibin share a number of their signaling components with a transduction cascade initiated by the TGFβ ligand. For example, both TGFβ and activin signal via the intracellular mediators, Smad2 and Smad3