Tzu-Hao Cheng

    PhD, Pharmacology, Rutgers University/UMDNJ, USA

    Post-doc, Genetics, Stanford University, USA

Research

  1. The cellular functions of human MDM2 isoforms which are regulated by alternative translation initiation

    MDM2 is an oncoprotein and its expression is de-regulated in a large fraction of cancer cells.  In addition to the full-length MDM2 protein migrating at the position of 90 kDa, there are several small MDM2 isoforms found in tumor cells.  The production of these isoforms could be mediated through alternative splicing of mdm2 transcripts, proteolytic processing of MDM2 protein, as well as alternative translation initiation of mdm2 mRNA that are transcribed from the P1 constitutive promoter.  Under normal condition, the transcription of mdm2 gene is derived from the P1 promoter and two MDM2 isoforms, p90MDM2 and p75MDM2, are detectable.  The small isoform lacks the p53 binding domain and its biological functions is not well understood.  In the laboratory, we are interested in the regulatory mechanisms which control the relative production of p75MDM2 to p90MDM2.  Additionally, we would like to explore the cellular functions of p75MDM2, especially for its roles in tumorigenesis.
     

  2. Cellular factors that contribute to mutant huntingtin protein aggregation

    Huntington disease is a neurodegenerative disorder that results from abnormal CAG expansion within the first exon of huntingtin gene.  As extended polyglutamine has an inherent propensity to form amyloid fibrils, the translation product of mutant hungtingtin gene with CAG repeats is aggregated and insoluble.  Recently, considerable evidences suggested that formation of aggregated protein is a critical determinant for cellular dysfunctions underlying Huntington disease.  Although polyglutamine (polyQ) become insoluble in vitro, cellular factors strongly modulate the formation and propagation of such aggregates in vivo.  Notably, polyQ aggregates in yeast, worms and mammalian cells can be modulated by HSP104, a yeast chaperone involved in thermal tolerance and disaggregation of misfolded proteins.  Elevated levels of Hsp70 chaperons can also ameliorate the effect of polyQ aggregation.  With current knowledge about polyQ aggregation, it uncovered that some but not all chaperon proteins are involved in this process.  It also suggested that accumulation of polyQ aggregates might be controlled by mechanisms which are distinct from conventional protein aggregation.  In order to understand this process in a great detail, we have established a genetic system to identify novel cellular factors that contribute to polyQ aggregation.                                                                    

 

Publications

  1. Cheng, T.H., Li, Y.C., and Gartenberg, M.R. (1998). Persistence of an alternate chromatin structure at silenced loci in the absence of silencers. Proc. Natl. Acad. Sci. USA 95, 5521-5526.
  2. Ansari A., Cheng, T.H., and Gartenberg, M.R. (1999). Isolation of chromatin rings from yeast employing site-specific recombination in vivo. Method: A Companion to Methods in Enzymology 17, 104-111.
  3. Cheng, T.H. and Gartenberg M.R. (2000). Yeast silent chromatin is a dynamic structure that requires silencers continuously. Genes & Dev. 14, 452-463.
  4. Cheng, T.H., Chang, C.R., Joy, P., Yablok, S., and Gartenberg, M.R. (2000). Controlling gene expression in yeast by inducible site-specific recombination. Nucleic Acids Res. 28, e108.
  5. Li, Y.C., Cheng, T.H., and Gartenberg, M.R. (2001). Establishment of transcriptional silencing in the absence of DNA replication. Science 291, 650-653.
  6. Chao, S.H., Cheng, T.H., Shaw, C.Y., Lee, M.H., Hsu, Y.H., and Tsai, Y.C. (2006) Characterization of a Novel PepF-Like Oligopeptidase Secreted by Bacillus amyloliquefaciens 23-7A. Appl. Enviro. Microbio. 72(1):23-27.
  7. Liu, C.R. and Cheng, T.H.(2006). Recombinant protein and method of screening for agents modulate polypeptide aggregation (U.S. patent pending)
  8. Cheng, T.H. and Cohen. S.N. (2007). Human MDM2 isoforms translated differentially on constitutive vs. p53-regulated transcripts have distinct functions in the p53/MDM2 and TSG101/MDM2 feedback control loops. Molecular and Cellular Biology (in print).
  9. Chua, H.H., Lee, H.H., Chang, S.S., Lu, C.C., Yeh, T.H., Hsu, T.Y., Cheng, T.H., Cheng, J.T., Chen, M.R., and Tsai, C.H. (2007). Role of TSG101 in Epstein-Barr viral late gene transcription. Journal of Virology (in pressed).