张义国，学者凯发k8国际首页主页-凯发网

main research interests in the transmembrane glycoprotein transcription factor nrf1
  
      oxidative stress is a crucial etiological factor leading to various chronic diseases, including cancer. the expression of antioxidant/detoxification genes is controlled principally by transcription factors nrf1, nrf2 and nrf3 and thus they can protect against the pathogenesis of oxidative stress-induced diseases. amongst them, nrf1 is essential for controlling the basal expression of antioxidant genes because global knockout of its gene in the mouse causes embryonic lethality and severe oxidative stress. moreover, adult liver-specific knockout of nrf1 results in nash-based inflammation and spontaneous hepatoma, and brain-specific nrf1 deletion leads to neurodegeneration by contrast, nrf2 is important in adaptation to stress because its knockout prevents induction of several antioxidant/detoxification genes. nrf3 does not appear to be essential due to no phenotype exhibited in knockout mice. these facts indicate that nrf1 fulfils an indispensable and unique biological function distinct from nrf2 and nrf3, and thus it represents a promising field to be explored in cancer research. it is a demanding challenge to study the biology and pathophysiology of nrf1, which has been identified as an inner nuclear membrane-bound glycoprotein factor that spatio-temporally activates or represses transcription of target genes responsible for carcinogenesis and chemoprevention. in addition, i have retained an interest in signalling transduction mechanisms of uv-induced skin cancer and prevention.

previous research experience
  
      1992-1999 in china: during the 3-year honours msc study, i had created monoclonal antibodies specifically against inhibin or activin using cell-fusion hybridoma technology and applied them in cancer pathological diagnosis. for the excellent thesis of 1995, i was appointed as a lecturer, teaching pathophysiology and cancer biology to undergraduates and postgraduates in the henan medical university (zhengzhou university), and also as a principal research assistant to professor ziming dong (from yale university) of cancer immunology, i had creatively developed various dentritic cells-based anticancer vaccines, and determined the anticancer immunopreventive effects and biomedical significance of therapy. from these translational studies, as the first and/or corresponding authors i had published 15 major research articles in chinese journals (written in chinese and english).
      1999-2003 in usa: to allow me to explore molecular mechanisms for skin cancer and prevention, i moved in the molecular and cellular biology group of professor zigang dong in university of minnesota. as a hormel research assistant, i developed research programme on uva-induced signalling transduction mechanisms for skin cell apoptosis, transformation or carcinogenesis. it is noteworthy that i first identified that uva (as a source of oxidative stress) triggered multiple signalling networks from egf receptor and membrane ceramide to mapks including erks, jnks, p38 kinase and their downstream kinases msk and rsk, and/or from phosphoinositde-3 kinases to pdk1, akt, mtor, and p70s6k, for protein translation controlled by pkr/perk-mediated eif2, towards gene regulation by a group of transcription factors, such as ap-1 dimers (c-jun, c-fos, atf2), stat1, stat3, nf-kb, p53 and smads. in addition, atm and atr are involved in these signalling networks. amongst these signalling molecules, key players in uva-induced skin carcinogenesis are considered as chemoprevention targets. for this topic, i have been very motivated and  published these studies in 9 of the first-authored articles in jbc and cancer-based journals. until now i have retained an interest in mechanisms of uv-induced skin cancer, as a recent research article has been in press of php, with the collaborator professor julia li zhong (chongqing university)
     2003-2010 in uk: for deeper insights in more detailed mechanisms for stress-induced carcinogenesis and antioxidant gene regulation, i was enlisted in professor hayes’ group at university of dundee in 2003. my phd study was completed in 2007, and continuing postdoctoral researches have focused on nrf1, and to a lesser extent on nrf2 and nrf3. i have discovered that nrf1 (and nrf3) is an integral transmembrane glycoprotein targeted into the endoplasmic reticulum (er), and sorted into the inner nuclear envelope membrane before target genes are transactivated in response to oxidative stress, but its activity is inhibited under er stress. i have identified structural domains in nrf1 and nrf3 in more detail, several of which are conserved in nrf2. these discoveries have been important, as very little or nothing is known of whether or how the neh2l region in nrf1 regulates spatiotemporally positioning of its activation domains and retrotransloction from the lumen into the nucleus, and then how nrf1 selectively controls its target genes. clearly, much remains to be done to elucidate the biological roles of nrf1 for its pathological phenotypes; significantly, liver-specific knockout of nrf1 in transgenic mice leads ultimately to spontaneous cancer. however, it is notable that the discoveries from my original work have provided excellent insights into the molecular and cell biology of nrf1 that will stand the field in good stead. the work achievements are embodied within 5 major publications in bj and jbc, as well as my book of expertise on nrf1, in which i am as the first and corresponding author.