Diffuse large B-cell lymphoma (DLBCL) consists of at least 2 phenotypic subtypes; that is, the germinal center B-celllike (GCB-DLBCL) and the activated Bcell-like (ABC-DLBCL) groups. It has been shown that GCB-DLBCL responds favorably to chemotherapy and expresses high levels of BCL6, a transcription repressor known to play a causative role in lymphomagenesis. In comparison, ABC-DLBCL has lower levels of BCL6, constitutively activated nuclear factor-B, and tends to be refractory to chemotherapy. Here, we report that the STAT3 gene is a transcriptional

IFN-1 (IL-29

No abstract

Mutations in the protein SIMPLE account for the rare autosomal-dominant demyelination in type 1C CMT patients (CMT1C). SIMPLE plays a role in the production of exosomes. Dysregulated endosomal trafficking and changes in exosome-mediated intercellular communications might account for CMT1C molecular pathogenesis.

ADP-ribosylation is a reversible posttranslational modification mediated by poly-ADP-ribose polymerase (PARP). The results of recent studies demonstrate that ADP-ribosylation contributes to transcription regulation. Here, we report that transcription factor NFAT binds to and is ADP-ribosylated by PARP-1 in an activation-dependent manner. Mechanistically, ADP-ribosylation increases NFAT DNA binding. Functionally, NFAT-mediated interleukin-2 (IL-2) expression was reduced in T cells upon genetic ablation or pharmacological inhibition of PARP-1. Parp-1 ؊/؊ T cells also exhibit reduced expression of other NFAT-dependent cytokines, such as IL-4. Together, these results demonstrate that ADP-ribosylation mediated by PARP-1 provides a molecular switch to positively regulate NFAT-dependent cytokine gene transcription. These results also imply that, similar to the effect of calcineurin inhibition, PARP-1 inhibition may be beneficial in modulating immune functions.ADP-ribosylation is a reversible posttranslational modification that transfers ADP-ribose from NAD ϩ to Glu, Asp, and/or Arg amino acids of target proteins (18). Similar to ubiquitination, ADP-ribosylation modifies target proteins to various masses due to the assorted chain lengths of the ADPribose. ADP-ribosylation is inhibited by the NAD ϩ analog 3-aminobenzamide and, more specifically, by PJ-34 (45). Poly-ADP-ribose polymerase-1 (PARP-1) is a nuclear enzyme that accounts for the bulk of ADP-ribosylation in vivo (43). Indeed, only ϳ10% of PARP activity remains in Parp-1 Ϫ/Ϫ cells upon DNA damage. In addition to its role in DNA damage repair, the results of recent studies demonstrate that PARP-1 contributes to gene transcription regulation (26,40).Transcription factor NFAT is the master regulator of interleukin-2 (IL-2) gene transcription (24,42). In resting cells, NFAT resides in the cytosol. The nuclear accumulation of NFAT is regulated by calcineurin-mediated dephosphorylation (9, 15, 23). The immunosuppressant drugs cyclosporine A (CsA) and tacrolimus (FK506) inhibit calcineurin and abrogate NFAT activation. Indeed, understanding the mechanism of NFAT activation has contributed to the great advances in transplantation surgery (27). Given that immunosuppressant therapy using CsA or FK506 causes neuro-and nephrotoxicity (1, 19), further understanding of the molecular basis of NFAT activation will provide alternate therapeutic targets for the treatment of transplant patients.Once in the nucleus, NFAT interacts with coregulators to achieve optimal NFAT activation (11,21,28). These NFAT coregulators include Fos-Jun, C/EBPs, and Fox3p, which form a composite transcription complex to regulate NFAT-mediated gene transcription. In addition, transcription coactivator CREBbinding protein/p300 and class II histone deacetylases are recruited to modulate NFAT-mediated transcription (3,12,16,48). Here, we report that PARP-1 binds to and ADP-ribosylates NFAT. The ADP-ribosylation mediated by PARP-1 provides a molecular switch to positively regulate NFAT-dependent cytokine ge...