31 research outputs found

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

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    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

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

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

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    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

    SUMO1 modification of NF-κB2/p100 is essential for stimuli-induced p100 phosphorylation and processing

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    A primary step in activating the alternative nuclear factor-κB (NF-κB) pathway requires NF-κB2/p100 processing to generate p52. In most cases, stimuli-induced p100 processing is dependent on NF-κB-inducing kinase/IκB kinase α-mediated phosphorylation and ubiquitination. Here, we report that post-translational modification of p100 at specific sites by the small ubiquitin-like modifier (SUMO) is another determining factor for stimuli-induced p100 processing. The results show that basal SUMO modification is required for stimuli-induced p100 phosphorylation and that blocking SUMOylation of p100, either by site-directed mutation or by short interfering RNA-targeted diminution of E2 SUMO-conjugating enzyme Ubc9, inhibits various physiological stimuli-induced p100 processing and ultimate activation of the alternative NF-κB pathway. Together, these findings show the crucial role of SUMO1 modification in p100 processing and provide mechanistic insights into the participation of SUMO1 modification in the regulation of signal transduction

    Human T-Cell Leukemia Virus Type I-Mediated Repression of PDZ-LIM Domain-Containing Protein 2 Involves DNA Methylation But Independent of the Viral Oncoprotein Tax1

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    Human T-cell leukemia virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). Our recent studies have shown that one important mechanism of HTLV-I-Mediated tumorigenesis is through PDZ-LIM domain-containing protein 2 (PDLIM2) repression, although the involved mechanism remains unknown. Here, we further report that HTLV-I-Mediated PDLIM2 repression was a pathophysiological event and the PDLIM2 repression involved DNA methylation. Whereas DNA methyltransferases 1 and 3b but not 3a were upregulated in HTLV-I-transformed T cells, the hypomethylating agent 5-aza-2′-deoxycytidine (5-aza-dC) restored PDLIM2 expression and induced death of these malignant cells. Notably, the PDLIM2 repression was independent of the viral regulatory protein Tax because neither short-term induction nor long-term stable expression of Tax could downregulate PDLIM2 expression. These studies provide important insights into PDLIM2 regulation, HTLV-I leukemogenicity, long latency, and cancer health disparities. Given the efficient antitumor activity with no obvious toxicity of 5-aza-dC, these studies also suggest potential therapeutic strategies for ATL
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