Graduate Studies Faculty
Mushui Dai, M.D., Ph.D.
Programs:Molecular & Medical Genetics
Program in Molecular & Cellular Biosciences
Research Interests:Tumor suppressor, p53, Oncogene, MDM2, c-Myc, Ribosomal biogenesis, Ribosomal proteins, Ubiquitination, Deubiquitinating enzymes. » Click here for more about Dr. Dai's research
Preceptor RotationsAcademic Term Available Spring 2014 Maybe Fall 2014 Maybe
Faculty MentorshipDr. Dai might be available as a mentor for 2013-2014.
Our broad research interest is to understand the biological function and molecular mechanisms of the p53 tumor suppression and c-Myc oncogenic pathways, thereby providing a possible means to manipulate p53 and c-Myc function in cancer cells.
Currently, we are working on three independent but related projects. (1). Control of p53 protein stability and activity by ubiquitination and deubiquitination. p53 is a short-lived protein and its activity is largely controlled in cells by modulating protein stability through ubiquitin-proteasome system. p53 is ubiquitinated and destabilized by MDM2 whereas it can be deubiquitinated and stabilized by the USP family members of deubiquitinating enzymes (DUBs) Hausp/USP7 and USP10. We recently found that the OTU family member of DUBs, Otubain 1 (Otub1), is a novel positive p53 regulator. Interestingly, Otub1 inhibits p53 ubiquitination through a unique non-canonical mechanism: suppressing the MDM2 (E3) cognate E2 (UbcH5) activity. Functionally, Otub1 plays a crucial role in p53 stability and activation following DNA damage. We are interested in characterizing the role of Otub1 in the p53 tumor suppressor pathway and further identifying other DUBs that could modulate the levels and activity of p53 in response to diverse stressors. (2) Ribosomal protein (RP) regulation of the MDM2-p53 feedback loop. We have demonstrated a critical role for several ribosomal proteins (L5, L11, L23, and S27a) in p53 activation in response to ribosomal stress via inhibiting MDM2. Interestingly, genetic alterations of several ribosomal proteins, including L5, L11, S27a, S19, and S14 are found in patients with Diamond-Blackfan Anemia (DBA) and several other forms of anemia syndromes with increased cancer susceptibility, suggesting that some RPs may possess tumor suppressor activity. We are currently investigating the mechanism(s) underlying the RP inhibition of the MDM2-p53 pathway. (3) Control of c-myc mRNA stability by ribosomal proteins. We have found that ribosomal protein L11 inhibits c-Myc transactivation activity by competing with TRRAP, a critical co-activator of c-Myc, for binding to c-Myc target gene promoters. Interestingly, we recently found that L11 also regulates c-myc mRNA stability through recruiting miR-24-loaded microRNA-induced silencing complex (miRISC) to the 3’-UTR of c-myc mRNA in response to ribosomal stress. We are currently further investigating the mechanisms and physiological significance of this L11 regulation of c-myc mRNA stability in response to stress.
Sun X.-X., Wang Y.-G., Xirodimas D.P., Dai M.-S. (2010) Perturbation of 60S ribosomal biogenesis results in ribosomal protein L5 and L11-dependent p53 activation. J Biol Chem, 285(33): 25812-25821
Sun X.-X., DeVine T., Challagundla K.B., Dai M.-S. (2011) Interplay between ribosomal protein S27a and MDM2 protein in p53 activation in response to ribosomal stress. J Biol Chem, 286(26): 22730-22741
Challagundla K.B., Sun X.-X., Zhang X., DeVine T., Zhang Q., Sears R.C., Dai M.-S. (2011) Ribosomal protein L11 recruits miR-24/miRISC to repress c-Myc in response to ribosomal stress. Mol Cell Biol, 31(19): 4007-4021
Sun X.-X., Challagundla K.B., Dai M.-S. (2012) Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1. EMBO J, 31(3): 576-592
DeVine T., Dai M.-S. (2013) Targeting the ubiquitin-mediated proteasome degradation of p53 for cancer therapy. Curr Pharm Des, 19(18): 3248-3262
Li Y., Sun X.-X., Elferich J., Shinde U., David L.L., Dai M.-S. (2014) Monoubiquitination is critical for ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (Otub1) to suppress UbcH5 enzyme and stabilize p53 protein. J Biol Chem, 289(8): 5097-5108