Human T-Cell Lymphotropic Virus: A Model of NF-κB-Associated Tumorigenesis

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL), whereas the highly related HTLV-2 is not associated with ATL or other cancers. In addition to ATL leukemogenesis, studies of the HTLV viruses also provide an exceptional model for understanding basic pathogenic mechanisms of virus-host interactions and human oncogenesis. Accumulating evidence suggests that the viral regulatory protein Tax and host inflammatory transcription factor NF-κB are largely responsible for the different pathogenic potentials of HTLV-1 and HTLV-2. Here, we discuss the molecular mechanisms of HTLV-1 oncogenic pathogenesis with a focus on the interplay between the Tax oncoprotein and NF-κB pro-oncogenic signaling. We also outline some of the most intriguing and outstanding questions in the fields of HTLV and NF-κB. Answers to those questions will greatly advance our understanding of ATL leukemogenesis and other NF-κB-associated tumorigenesis and will help us design personalized cancer therapies

Lithium promotes neural precursor cell proliferation: evidence for the involvement of the non-canonical GSK-3β-NF-AT signaling

Lithium, a drug that has long been used to treat bipolar disorder and some other human pathogenesis, has recently been shown to stimulate neural precursor growth. However, the involved mechanism is not clear. Here, we show that lithium induces proliferation but not survival of neural precursor cells. Mechanistic studies suggest that the effect of lithium mainly involved activation of the transcription factor NF-AT and specific induction of a subset of proliferation-related genes. While NF-AT inactivation by specific inhibition of its upstream activator calcineurin antagonized the effect of lithium on the proliferation of neural precursor cells, specific inhibition of the NF-AT inhibitor GSK-3β, similar to lithium treatment, promoted neural precursor cell proliferation. One important function of lithium appeared to increase inhibitory phosphorylation of GSK-3β, leading to GSK-3β suppression and subsequent NF-AT activation. Moreover, lithium-induced proliferation of neural precursor cells was independent of its role in inositol depletion. These findings not only provide mechanistic insights into the clinical effects of lithium, but also suggest an alternative therapeutic strategy for bipolar disorder and other neural diseases by targeting the non-canonical GSK-3β-NF-AT signaling

Identification and characterization of novel NF-kB dependent genes involved in HTLV-I pathogenesis

The NF-kB transcription factor plays pivotal roles in the pathogenesis and therapy-resistance of human cancers, including adult T-cell leukemia (ATL) induced by the oncoretrovirus HTLV-I. However, the downstream target genes of NF-kB involved in cancer biology and therapy remain largely unknown. To address this important issue, we have developed a novel approach called subtraction-based complementary gene expression cloning strategy. Given the characteristic anti-apoptosis activity of cancer cells, we used this approach to identify NF-kB-dependent anti-apoptotic genes involved in HTLV-I oncogenesis. The principle of this strategy is that expression of anti-apoptotic genes induced by HTLV-I-activated NF-kB should protect normal T cells from apoptosis induced by death inducers such as FasL. Briefly, a subtractive cDNA retroviral library enriched in genes induced by HTLV-I-NF-kB was generated and used to infect FasL-sensitive T cells. The infected T cells were treated with FasL and G418 (selective marker of cDNA expression). The FasL-and G418-resistant clones were isolated by limiting dilution, and the functional genes involved in FasL-resistance were fished out by RT-PCR and DNA sequencing. Using this strategy, several known NF-kB-dependent apoptotic genes have been identified, such as IAP1, Bcl-xL, c-FLIP and DcR2, indicating the reliability of our approach. Notably, numerous novel NF-kB-dependent anti-apoptotic genes were also identified. One of these novel genes has been confirmed to be expressed highly in HTLV-I-transformed T cells and primary ATL cells, and can be induced in normal T cells by HTLV-I in an NF-kB-dependent manner. Our mechanistic studies further indicate that this novel protein binds to mitochondria and prevents FasL activation of Bid, Caspase 9 and Caspase 3 but not Caspase 8. Currently, we are actively investigating the pathophysiological role of this novel gene in the biology and therapy of ATL and other cancers associated with deregulated NF-kB

An artificial bee colony-based hybrid approach for waste collection problem with midway disposal pattern

This paper investigates a waste collection problem with the consideration of midway disposal pattern. An artificial bee colony (ABC)-based hybrid approach is developed to handle this problem, in which the hybrid ABC algorithm is proposed to generate the better optimum-seeking performance while a heuristic procedure is proposed to select the disposal trip dynamically and calculate the carbon emissions in waste collection process. The effectiveness of the proposed approach is validated by numerical experiments. Experimental results show that the proposed hybrid approach can solve the investigated problem effectively. The proposed hybrid ABC algorithm exhibits a better optimum-seeking performance than four popular metaheuristics, namely a genetic algorithm, a particle swarm optimization algorithm, an enhanced ABC algorithm and a hybrid particle swarm optimization algorithm. It is also found that the midway disposal pattern should be used in practice because it reduces the carbon emission at most 7.16% for the investigated instances

PDLIM2 restricts Th1 and Th17 differentiation and prevents autoimmune disease

Background: PDLIM2 is essential for the termination of the inflammatory transcription factors NF-κB and STAT but is dispensable for the development of immune cells and immune tissues/organs. Currently, it remains unknown whether and how PDLIM2 is involved in physiologic and pathogenic processes. Results: Here we report that naive PDLIM2 deficient CD4+ T cells were prone to differentiate into Th1 and Th17 cells. PDLIM2 deficiency, however, had no obvious effect on lineage commitment towards Th2 or Treg cells. Notably, PDLIM2 deficient mice exhibited increased susceptibility to experimental autoimmune encephalitis (EAE), a Th1 and/or Th17 cell-mediated inflammatory disease model of multiple sclerosis (MS). Mechanistic studies further indicate that PDLIM2 was required for restricting expression of Th1 and Th17 cytokines, which was in accordance with the role of PDLIM2 in the termination of NF-κB and STAT activation. Conclusion: These findings suggest that PDLIM2 is a key modulator of T-cell-mediated immune responses that may be targeted for the therapy of human autoimmune diseases