IGF-I and IGFBP-3 expression increase during human preadipocyte differentiation. However, whereas IGF-I stimulates this process, IGFBP-3 is inhibitory both to preadipocyte differentiation and to differentiated adipocyte function. The direct interaction of IGFBP-3 with peroxisome proliferator-activated

receptor-gamma is believed to contribute to its inhibitory effect on differentiation. Connective tissue growth factor (CTGF/CCN2) shares weak structural homology and functional similarities with IGFBP-3, including inhibition of preadipocyte differentiation. This review examines the current knowledge of IGFBP regulation and actions in adipocytes and proposes a common regulatory pathway involving IGFBP-3 and CTGF/CCN2.”
“We recently provided evidence that the ribonucleotide reductase

R1 subunits TGF-beta inhibitor of herpes OSI-744 order simplex virus types 1 and 2 (HSV-1 and -2) protect cells against tumor necrosis factor alpha-and Fas ligand-induced apoptosis by interacting with caspase 8. Double-stranded RNA (dsRNA) is a viral intermediate known to initiate innate antiviral responses. Poly(I center dot C), a synthetic analogue of viral dsRNA, rapidly triggers caspase 8 activation and apoptosis in HeLa cells. Here, we report that HeLa cells after HSV-1 and HSV-2 infection were quickly protected from apoptosis caused by either extracellular poly(I center 3-mercaptopyruvate sulfurtransferase dot C) combined with cycloheximide or transfected poly(I center dot C). Cells infected with the HSV-1 R1 deletion mutant ICP6 Delta were killed by poly(I center dot C), indicating that HSV-1 R1 plays a key role in antiapoptotic responses to poly(I center dot C). Individually expressed HSV R1s counteracted caspase 8 activation by poly(I center dot C). In addition to their binding to caspase

8, HSV R1s also interacted constitutively with receptor-interacting protein 1 (RIP1) when expressed either individually or with other viral proteins during HSV infection. R1(1-834)-green fluorescent protein (GFP), an HSV-2 R1 deletion mutant protein devoid of antiapoptotic activity, did not interact with caspase 8 and RIP1, suggesting that these interactions are required for protection against poly(I center dot C). HSV-2 R1 inhibited the interaction between the Toll/interleukin-1 receptor domain-containing adaptor-inducing beta interferon (IFN-beta) (TRIF) and RIP1, an interaction that is essential for apoptosis triggered by extracellular poly(I center dot C) plus cycloheximide or TRIF overexpression. TRIF silencing reduced poly(I center dot C)-triggered caspase 8 activation in mock-and ICP6 Delta-infected cells, confirming that TRIF is involved in poly(I center dot C)-induced apoptosis. Thus, by interacting with caspase 8 and RIP1, HSV R1s impair the apoptotic host defense mechanism prompted by dsRNA.