Yan, Mingshan

Yan, Mingshan MD., PhD.

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Research Interests

Retrovirus-induced neurodegeneration and its prevention with antioxidants, Ataxia Telangiectasia Mutated (ATM) in thymocyte development and lymphoid tumorigenesis

Current Research

  1. 1. The role of Reactive Oxygen Species in retrovirus-induced neurodegeneration and immunodeficiency
    The retrovirus ts1, a temperature-sensitive mutant of Moloney murine leukemia retrovirus, resembles human HIV-1 and induces neurodegeneration in FVB/N mice. Using the ts1-infected animal model, we have identified that oxidative stress is a major mechanism in the pathogenesis ts1 induced neurodegeneration. ts1 infects immune cells and astrocytes, and causes ER stress and mitochondrial damage, which increase intracellular ROS production, resulting in apoptosis in infected cells. Administration of antioxidants and some anti-inflammatory agents, such as N-acetylcysteine (NAC), GVT and minocycline, can reduce ROS accumulation, thereby delaying ts1-induced neurodegeneration in treated mice. In C1 astrocyte line, ts1 infection activates p53 phosphorylation at serine 15. This action of ts1 may be contributed to its ability to induce ROS production and accumulation in C1 cells since antioxidant NAC treatment diminished ts1-induced p53 activation. In addition, ATM, MAPK and mTOR are also involved in ts1-induced neurodegeneration. Our overall objective is to understand how ts1 induces ROS, by which cell signaling pathway ROS causes neurodegeneration, whether antioxidants such as GVT, NAC amide prevent ts1-induced neurodegeneration in the animal model.
  2. 2. ATM, ROS, DNA synthesis and c-Myc in thymocyte development and lymphoid tumorigenesis
    ATM is a multifunctional protein kanase that regulates cell cycling and cellular responses to events that damage DNA. When activated, ATM undergoes autophosphorylation, and in this form it initiates phosphorylation of multiple substrates, including p53. ATM also regulates intracellular redox state. In ATM knockout (Atm-/-) mice and A-T humans, fatal thymic lymphomas commonly develop early in life, but the mechanisms leading to this symptom are not clear. Our first study with this model disclosed that the spontaneous DNA synthesis is markedly increased in Atm-/- thymocytes. In later work, we learnt that the increased DNA synthesis represents a failure of T cells to develop and differentiation, which eventually produce thymic atrophy (immunodeficiency), apoptosis, and tumorigenesis. Treatment with glucocorticoid dexamethasone suppresses the elevated DNA synthesis, and prevents thymic lymphoma development in Atm-/- mice. Our recent data showed that oncoprotein c-Myc levels are progressively increased in Atm-/- thymocytes, and this increased c-Myc levels parallel the elevated DNA synthesis in the cells, suggesting that ATM check DNA synthesis during thymocyte development through counteracting c-Myc signaling. Again, administration of NAC attenuates the elevated DNA synthesis and c-Myc levels in Atm-/- mice. We are now focusing on the network among ATM, ROS, DNA synthesis and c-Myc in thymocyte development and lymphoid tumorigenesis.

Selected Publications

  1. Jiang Y, Scofield VL, Yan M, Qiang W, Liu N, Reid AJ, Lynn WS, Wong PK. Retrovirus-induced oxidative stress with neuroimmunodegeneration is suppressed by antioxidant treatment with a refined monosodium alpha-luminol (Galavit), J Virol, 80 (9), 4557-69, 2006
  2. Pusapati RV, Rounbehler RJ, Hong S, Powers JT, Yan M, Kiguchi K, McArthur MJ, Wong PK, Johnson DG. ATM promotes apoptosis and suppresses tumorigenesis in response to Myc, Proc Natl Acad Sci U S A, 103 (5), 1446-51, 2006
  3. Yan M, Zhu C, Liu N, Jiang Y, Scofield VL, Riggs PK, Qiang W, Lynn WS, Wong PK. ATM controls c-Myc and DNA synthesis during postnatal thymocyte development through regulation of redox state, Free Radic Biol Med, 41 (4), 640-8, 2006
  4. Kuang X, Yan M, Liu N, Scofield VL, Qiang W, Cahill J, Lynn WS, Wong PK. Control of Atm-/- thymic lymphoma cell proliferation in vitro and in vivo by dexamethasone, Cancer Chemother Pharmacol, 55 (3), 203-12, 2005
  5. Yan M, Kuang X, Qiang W, Shen J, Claypool K, Lynn WS, Wong PK. Prevention of thymic lymphoma development in atm-/- mice by dexamethasone, Cancer Res, 62 (18), 5153-7, 2002
  6. Yan M, Qiang W, Liu N, Shen JJ, Lynn WS, Wong PK. The ataxia-telangiectasia gene product may modulate DNA turnover and control cell fate by regulating cellular redox in lymphocytes, Faseb J, 15 (7), 1132-8, 2001

Contact Information


Mailing Address: P.O. Box 389, Smithville, Texas 78957
Physical Address: 1808 Park Road 1C, Smithville, Texas 78957
Phone: (512) 237-9452