The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4؉ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30 II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30 II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30 II /Myc-TIP60 chromatin-remodeling complexes. The p30 II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30 II interact with the TIP60 HAT, and p30 II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30 II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis.

Transforming growth factor ␤ (TGF-␤) plays a critical role in tissue fibrosis. The duration and intensity of TGF-␤ signaling are tightly regulated. Here we report that TSC-22 (TGF-␤-stimulated clone 22) facilitates TGF-␤ signaling by antagonizing Smad7 activity to increase receptor stability. TSC-22 enhances TGF-␤-induced Smad2/3 phosphorylation and transcriptional responsiveness. The stimulatory effect of TSC-22 is dependent on Smad7, as silencing Smad7 expression abolishes it. TSC-22 interacts with TGF-␤ type I receptor T␤RI and Smad7 in mutually exclusive ways and disrupts the association of Smad7/Smurfs with T␤RI, thereby preventing ubiquitination and degradation of the receptor. We also found that TSC-22 can promote the differentiation of cardiac myofibroblasts by increasing expression of the fibrotic genes for ␣-smooth muscle actin (␣-SMA), PAI-1, fibronectin, and collagen I, which is consistent with upregulation of TSC-22, phospho-Smad2/3, and the fibrotic genes in isoproterenol-induced rat myocardial fibrotic hearts. Taken together with the notion that TGF-␤ induces TSC-22 expression, our findings suggest that TSC-22 regulates TGF-␤ signaling via a positive-feedback mechanism and may contribute to myocardial fibrosis.

Highlights d PPP1R3G is directly phosphorylated by AKT in response to insulin or feeding d PPP1R3G phosphorylation accelerates postprandial glycogenesis and glucose clearance d Phosphorylation of PPP1R3G enhances its association with p-GS d PPP1R3B acts downstream of PPP1R3G to relay insulin signals for glycogen synthesis

The incidence of gastric cancer (GC) is extremely high in East Asia. GC is also one of the most common and lethal forms of cancer from a global perspective. However, to date, we have not been able to determine one or several genes as biomarkers in the diagnosis of GC and have also been unable to identify the genes which are important in the therapy of GC. In this study, we analyzed all genome-wide expression profiling arrays uploaded onto the Gene Expression Omnibus (GEO) database to filtrate the differentially expressed genes (DEGs) between normal stomach tissues and GC tissues. GSE13911, GSE19826 and GSE79973 were based on the GPL570 platform, and GSE29272 was based on the GPL96 platform. We screened out the DEGs from the two platforms and by selecting the intersection of these two platforms, we identified the common DEGs in the sequencing data from different laboratories. Finally, we obtained 3 upregulated and 34 downregulated DEGs in GC from 384 samples. As the number of downregulated DEGs was greater than that of the upregulated DEGs, functional analysis and pathway enrichment analysis were performed on the downregulated DEGs. Through our analysis, we identified the most significant genes associated with GC, such as secreted phosphoprotein 1 (SPP1), sulfatase 1 (SULF1), thrombospondin 2 (THBS2), ATPase H+/K+ transporting beta subunit (ATP4B), gastric intrinsic factor (GIF) and gastrokine 1 (GKN1). The prognostic power of these genes was corroborated in the Oncomine database and by Kaplan-Meier plotter (KM-plotter) analysis. Moreover, gastric acid secretion, collecting duct acid secretion, nitrogen metabolism and drug metabolism were significantly related to GC. Thus, these genes and pathways may be potential targets for improving the diagnosis and clinical effects in patients with GC.