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Gutian Xiao, Ph.D.
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Associate Professor
1.8 HCCLB
5117 Centre Avenue
Pittsburgh, Pennsylvania 15213
Phone: (412) 623-5410
Fax: (412) 623-2525
E-mail: gux8@pitt.edu
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Research
Our primary research interests are the study of signaling transduction pathways in immunity and tumorigenesis, particularly autophagy and NF-κB, as well as the molecular mechanisms underlying the type-1 human T cell leukemia virus (HTLV-I) mediated T cell transformation for disease preventive and therapeutic purposes.
Autophagy is one of the two major mechanisms for protein degradation in all the eukaryotes including mammals. By controlling both quality and quantity of proteins and organelles, autophagy plays key roles in various physiological and pathogenic processes, such as cellular homeostasis, development, cell survival, aging, neurodegeneration, inflammation and immune responses. Recently, an essential role of autophagy in tumor suppression has also been clearly demonstrated by both biochemical and genetic evidences: 1. Autophagy is induced in tumors by many anti-tumor agents including rapamycin, tamoxifen, arsenic trioxide and radiation, resulting in tumor cell death; 2. Many oncoproteins and protooncoproteins, such as AKT, mTOR, PI3K and IKK, are potent inhibitors of autophagy while many tumor suppressors, such as PTEN, are activators of autophagy; 3. Most importantly, loss of Beclin 1, UVRAG or Bif-1 leads to tumor formation in both animal and human whereas enforced expression of Beclin 1 or Atg5 (autohagy related gene 5) inhibits tumor growth and increases efficacy of anti-tumor drugs in vivo. Beclin 1, UVRAG, Bif-1 and Atg5 are essential regulators of autophagy. Our studies also indicate that fibroblast cells genetically deficient in Atg5 show tumorigenicity. However, the mechanisms by which autophagy inhibits tumorigenesis are unclear. In addition, the mechanisms by which autophagy is regulated are still largely unknown.
Contrast to autophagy, NF-κB plays a causative role in tumorigenesis and tumor resistance to cancer therapy. NF-κB is a family of transcription factors that control expression of numerous genes involved in diverse biological processes, including inflammation, immune response, and cell survival. NF-κB activity is normally inhibited by IκB (Inhibitor of NF-κB) or IκB-like protein p100. Accordingly, NF-κB activation requires IκB degradation or p100 processing to selectively degrade the IκB-like inhibitory fragment within p100 C-terminal. The IκB degradation depends on an IκB kinase (IKK) complex, which consists of IKKα, IKKβ (two catalytic subunits) and IKKγ (regulatory subunit), while the p100 processing is specifically mediated by IKKα and its upstream kinase NIK, NF-κB-inducing kinase. Right now, these two major pathways leading to NF-κB activation are termed as canonical and non-canonical NF-κB signaling, respectively. Abnormally persistent activation of either pathway will lead to various pathogenic conditions, particularly chronic inflammation, autoimmune diseases and cancers. However, how NF-κB is activated under pathogenic conditions and how NF-κB contributes to the pathogenesis keep elusive.
HTLV-I is an oncogenic retrovirus etiologically associated with the development of adult T-cell leukemia (ATL) and neurodegeneration. HTLV-I-induced pathogenesis is largely mediated by the virus encoded oncoprotein Tax. Interestingly, the oncogenic ability of Tax requires NF-κB. As a matter of fact, NF-κB activation by Tax is sufficient for tumorigenesis. Therefore, Tax-mediated NF-κB represents one of the best characterized and most easily studied model systems for understanding NF-κB signaling and NF-κB-mediated pathogenesis.
Fortunately enough, the mechanisms by which the non-canonical NF-κB is regulated under both physiological and HTLV pathogenic conditions were first and largely described by us together with our collaborators. Recently, our group has demonstrated not only a novel mechanism for NF-κB activation under a different pathogenic condition but also an essential and sufficient role of p100 processing in various tumorigenesis. These studies provide a first line of evidence for the endoproteolytic activity of the proteasome and a unique mode for the proteasome-mediated transcription regulation. More recently, our group has defined, for the first time, a direct link among autophagy, NF-κB, mTOR and Hsp90. These works have had very significant impacts by demonstrating that NF-κB activation is fundamentally different under physiological and pathogenic conditions, opening new research avenues for autophagy, NF-κB, mTOR and Hsp90 fields, and changing some dogmas in these fields. Although it is clear that NF-κB is involved in various human diseases, it is challenging to use general NF-κB inhibitors as drugs, because NF-κB is also essential for many basic cellular functions of normal cells. Our work has thus provided the molecular basis for developing effective medicines with no or low but tolerable toxicity.
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Selected Publications
- Vatsyayan J, Qing G, Xiao G, Hu J. 2008. "SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing" EMBO Rep. 9:885-90. | Abstract
- Yan P., Qing G., Qu Z., Wu C.-C., Rabson A., and Xiao G. (2007) Targeting autophagic regulation of NF-κB activation in HTLV-I transformed cells by geldanamycin: Implications for therapeutic interventions. Autophagy 3(6): 600-603. | Abstract
- Qing G, Yan P, Qu Z, Liu H, Xiao G. 2007. "Hsp90 regulates processing of NF-kappa B2 p100 involving protection of NF-kappa B-inducing kinase (NIK) from autophagy-mediated degradation" Cell Res.17:520-30. | Abstract
- Qing G, Qu Z, Xiao G. 2007. "Endoproteolytic processing of C-terminally truncated NF-kappaB2 precursors at kappaB-containing promoters" Proc Natl Acad Sci USA. 104:5324-9. | Abstract
- Xiao G. 2007. "Autophagy and NF-κB: Fight for fate" Cytokine & Growth Factor Rev. 18:233-243. | Abstract
- Qing G., Yan P., and Xiao G. 2006. "Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IκB kinase (IKK)" Cell Res. 16: 895-901. | Abstract
- Xiao G., Rabson A., Young W., Qing G., and Qu Z. (2006) Alternative pathways of NF-κB activation: a double-edged sword in health and disease. Cytokine & Growth Factor Rev. 17(4): 281-293. | Abstract
- Qing G., Qu Z., and Xiao G. (2005) Stabilization of NF-κB-inducing kinase (NIK) functions as a molecular switch of NF-κB2 p100 processing. J. Biol. Chem. 280(49): 40578-40582. | Abstract
- Qing G., Qu Z., and Xiao G. (2005) Regulation of NF-κB2 p100 processing involves its cis-acting domain. J. Biol. Chem. 280(1):18-27. | Abstract
- Qu Z., Qing G., Rabson A., and Xiao G. (2004) Tax deregulation of p100 processing involves both κ-TrCP-dependent and independent mechanisms. J. Biol. Chem. 279(43): 44563-44572. | Abstract
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