The mechanisms by which the human T-cell leukemia virus type I (HTLV-I) Tax oncoprotein deregulates cellular signaling for oncogenesis have been extensively studied, but how Tax itself is regulated remains largely unknown. Here we report that Tax was negatively regulated by PDLIM2, which promoted Tax K48-linked polyubiquitination. In addition, PD-LIM2 recruited Tax from its functional sites into the nuclear matrix where the polyubiquitinated Tax was degraded by the proteasome. Consistently, PDLIM2 suppressed Tax

IntroductionThe nuclear factor B (NF-B) family of transcription factors plays a central role in regulation of diverse biologic processes, including immune responses, cell growth, and, cell survival. 1 The NF-B factors are usually sequestered in the cytoplasm as latent complexes through physical interaction with the inhibitors of B (IB), mainly IB␣ and the IB-like protein p100 (the precursor of the mature form of NF-B2, p52). Accordingly, inducible degradation of IB␣ and selective degradation of the C-terminal IB-like sequences of p100 (processing) to generate p52 represent 2 major mechanisms leading to NF-B activation: the canonical and noncanonical NF-B pathways, respectively.In the canonical NF-B pathway, IB␣ degradation requires inducible phosphorylation at serines S32 and S36 by a specific IB kinase (IKK) complex that consists of 2 catalytic components, IKK␣ (also known as IKK1) and IKK␤ (or IKK2), and a regulatory subunit, IKK␥ (NEMO). IKK-mediated phosphorylation results in rapid ubiquitination and proteasomal degradation of IB␣, allowing RelA (the prototypic member of NF-B, also known as p65) and other NF-B members to localize to the nucleus to induce gene expression. 1 In the noncanonical NF-B pathway, IKK␣ is specifically recruited into the p100 complex to phosphorylate p100, leading to p100 ubiquitination and processing to p52. The newly generated p52 together with NF-B binding partners then translocates into the nucleus, where they induce or repress gene expression. [2][3][4] Through deregulation of its target genes, NF-B has been linked to various malignancies, such as adult T-cell leukemia (ATL) caused by the human T-cell leukemia virus type I (HTLV-I). 1 This retrovirus encodes a viral oncoprotein Tax, known to persistently activate both the canonical and noncanonical NF-B pathways. Tax binds to and activates IKK via IKK␥ to phosphorylate IB␣, resulting in IB␣ degradation and RelA nuclear translocation. [5][6][7][8][9] Recent studies suggested that posttranslational modifications of Tax, such as ubiquitination, are required for Tax binding to IKK␥ and subsequent IKK activation. [10][11][12] Another important function of Tax in the activation of the canonical NF-B pathway is to promote IKK␣ to phosphorylate S536 of RelA, which is required for RelA transcriptional activity. 13,14 In parallel, Tax specifically recruits IKK␣ into the p100 complex to activate the noncanonical NF-B pathway. 15,16 Although the mechanisms of how the canonical and noncanonical NF-B pathways are regulated and activated under both physiologic and pathogenic conditions have been extensively studied, it remains largely unknown whether and how the 2 NF-B signaling pathways cooperate, particularly during tumorigenesis.The WW domain-containing oxidoreductase (WWOX) gene, also known as WOX1 or FOR, which is located at the second most common human fragile site, FRA16D, has been linked to many different cancer conditions, including leukemia and lymphomas. 17,18 Recent evidence from both biochemical and genetic studies has clearly ...

Constitutive activation of the nuclear factor-κB (NF-κB) transcription factor plays a key role in chronic colonic inflammation and colon tumorigenesis. However, the mechanisms by which the tightly regulated NF-κB pathway becomes constitutively activated during colonic pathogenesis remain obscure. Here, we report that PDLIM2, an essential terminator of NF-κB activation, is repressed in various human colorectal cancer cell lines, suggesting one important mechanism for the constitutive activation of NF-κB. Indeed, expression of exogenous PDLIM2 inhibited constitutive NF-κB activation in these colorectal cancer cells. Importantly, the PDLIM2 expression was sufficient to suppress in vitro anchorage-independent growth and in vivo tumor formation of these malignant cells. We have further shown that the PDLIM2 repression involves promoter methylation. Accordingly, treatment of the colorectal tumor cell lines with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine restored PDLIM2 expression and resulted in growth arrest. These studies thus provide new mechanistic insights into colon tumorigenesis by identifying a novel tumor suppressor role for PDLIM2. Cancer Res; 70(5); 1766-72. ©2010 AACR.

Fbw7 is a ubiquitin-ligase that targets several oncoproteins for proteolysis, but the full range of Fbw7 substrates is not known. Here we show that by performing quantitative proteomics combined with degron motif searches, we effectively screened for a more complete set of Fbw7 targets. We identify 89 putative Fbw7 substrates, including several disease-associated proteins. The transcription factor NF-κB2 (p100/p52) is one of the candidate Fbw7 substrates. We show that Fbw7 interacts with p100 via a conserved degron and that it promotes degradation of p100 in a GSK3β phosphorylation-dependent manner. Fbw7 inactivation increases p100 levels, which in the presence of NF-κB pathway stimuli, leads to increased p52 levels and activity. Accordingly, the apoptotic threshold can be increased by loss of Fbw7 in a p100-dependent manner. In conclusion, Fbw7-mediated destruction of p100 is a regulatory component restricting the response to NF-κB2 pathway stimulation.

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The NF-B transcription factor plays a pivotal role in breast cancer progression and therapy resistance. However, the mechanisms by which the tightly regulated NF-B becomes constitutively activated during breast cancer pathogenesis remain obscure. Here, we report that PDZ-LIM domain-containing protein 2 (PDLIM2), an essential terminator of NF-B activation, is repressed in both estrogen receptor-positive and estrogen receptor-negative breast cancer cells, suggesting one important mechanism for the constitutive activation of NF-B. Indeed, PDLIM2 reexpression inhibited constitutive NF-B activation and expression of NF-B-targeted genes in those breast cancer cells. Importantly, PDLIM2, but not its mutants defective in NF-B termination, could suppress in vitro anchorage-independent growth and in vivo tumor formation of those malignant breast cells. In addition, we have shown that PDLIM2 repression involves promoter methylation. Accordingly, treatment of the breast cancer cells with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine reverses the methylation of the PDLIM2 promoter, restored PDLIM2 expression, and suppressed tumorigenicities of human breast cancer cells both in vitro and in vivo. These studies thus provide important mechanistic insights into breast cancer pathogenesis. These studies also suggest a tumor suppression function of PDLIM2 and a therapeutic strategy for breast cancer.Breast cancer has the highest incidence among women in the Western world, affecting more than 12% of women and accounting for 15% of all cancer deaths in women (1). In addition, although breast cancer is relatively rare in men, both the incidence and the death rate of male breast cancer remain one percentile compared with those of female breast cancer. The limitation on better treatments for this malignancy is largely due to lack of knowledge on the molecular mechanism of how breast cancer proceeds to become an invasive tumor that is resistant to cancer therapies.Recent studies have suggested that NF-B, a transcription factor essential for inflammatory and immune response, plays a pivotal role in the biology and therapy resistance of breast cancer (2-4). For example, constitutive activation of its prototypic member RelA/p65 has been shown to be important for the development and progression of breast cancer and therefore resistant to cancer therapies (5, 6). However, NF-B activation is tightly controlled under physiological conditions (7). In resting, nonstimulated cells, NF-B is sequestered in the cytoplasm by specific inhibitors, the IB proteins (mainly IB␣). In response to a variety of stimuli, including microbial infection and proinflammatory cytokines, the NF-B-bound IB␣ is quickly phosphorylated, ubiquitinated, and degraded, allowing liberated NF-B to enter the nucleus for gene transcription. Besides induction of proinflammatory cytokines, and cell proliferation and survival genes, nuclear NF-B also induces expression of IB␣, which in turn enters the nucleus and shuttles the activated NF-B back to the cytoplasm to reco...

Background & Aims Increased nut consumption has been associated with reduced inflammation, insulin resistance, and oxidative stress. Although these factors are closely involved in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD), few studies have focused on the association between nut consumption and NAFLD in the general population. We aimed to investigate the association of nut consumption and NAFLD in an adult population. Methods A total of 23 915 participants from Tianjin Chronic Low‐Grade Systemic Inflammation and Health (TCLSIH) Cohort Study were included in this study. Information on dietary intake was collected using a validated food frequency questionnaire. Abdominal ultrasonography was done to diagnose NAFLD. Multivariable logistic regression was used to assess the association of nut consumption with NAFLD. Results After adjusting for sociodemographic, medical, dietary, and lifestyle variables, the odds ratios (95% confidence interval) for NAFLD across categories of nut consumption were 1.00 (reference) for <1 time/week, 0.91 (0.82, 1.02) for 1 time/week, 0.88 (0.76, 1.02) for 2‐3 times/week, and 0.80 (0.69, 0.92) for ≥4 times/week (P for trend < 0.01). These associations were attenuated but remained significant after further adjustment for blood lipids, glucose, and inflammation markers. Conclusions Higher nut consumption was significantly associated with lower prevalence of NAFLD. Further prospective studies and randomized trials are required to ascertain the causal association between nut consumption and NAFLD.

Summary Objective Handgrip strength (HGS) begins an accelerating decline around 50 years. Many of the studies performed in old adults have demonstrated a significant relationship between vitamin D and HGS, but the studies performed in participants with a broad age range have yielded conflicting results. The purpose of the study was to investigate the relationship between vitamin D and HGS using age 50 as a specific cut‐off. Design Population‐based, cross‐sectional study. Participants Totally 5102 participants (2911 males, 2191 females) from the TCLSIH Cohort. Measurements Serum concentration of 25‐hydroxyvitamin D (25(OH)D) was measured using an enzyme immunoassay. We divided participants into quartiles according to 25(OH)D, and the ranges for increasing quartiles were as follows: (males [≥50 years]: 10.94‐31.85, 31.88‐43.01, 43.20‐56.06, 56.20‐143.0; males [<50 years]: 11.11‐34.68, 34.71‐46.91, 46.96‐59.45, 59.50‐143.7; females [≥50 years]: 7.21‐30.01, 30.02‐40.18, 40.21‐52.44, 52.49‐275.4; females [<50 years]: 5.29‐28.91, 28.92‐40.19, 40.20‐51.90, 51.91‐140.2). HGS was measured with a hydraulic hand‐held dynamometer. Analysis of covariance was employed to explore the relationship. Results Among males aged above 50 years, the means (95% confidence interval) for HGS per body weight across the categories of serum 25(OH)D concentration were 0.523 (0.430‐0.638), 0.545 (0.447‐0.664), 0.543 (0.446‐0.661), 0.546 (0.449‐0.664) (Ptrend < 0.01) after adjustment for potential confounding factors. However, no relationships were observed between serum 25(OH)D concentration and HGS in males aged below 50 years and females in the whole age range. Conclusions Serum 25(OH)D concentration was significantly related to HGS in males aged above 50 years, independent of confounding factors. Future studies are needed to clarify the age and sex relationship between serum 25(OH)D concentration and HGS.