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 Fall 2015 Yes Winter 2016 Yes Spring 2016 Yes
Faculty MentorshipDr. Dai is available as a mentor for 2015-2016.
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 several 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 several USP family members of deubiquitinating enzymes (DUBs), such as Hausp/USP7, USP10 and USP42. We have 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). Regulation of c-Myc protein stability and activity by ubiquitination and deubiquitination. The c-Myc oncoprotein is also a short-lived protein. Its stability and activity are tightly regulated by the ubiquitin-proteasome system. Aberrant stabilization of c-Myc contributes to many human cancers. c-Myc is ubiquitinated by SCFFbw7(a SKP1-cullin-1-F-box complex that contains the F-box protein Fbw7) and several other ubiquitin ligases, whereas it is deubiquitinated and stabilized by USP28 in the nucleus. Yet, the bulk of c-Myc degradation appears to occur in the nucleolus. We recently identified that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with c-Myc and the nucleolar Fbw7γ, forming a tertiary complex in the nucleolus. It directly deubiquitinates and stabilizes c-Myc in cells and is essential for cancer cell proliferation. Consistently, USP36 is overexpressed in a subset of tested human breast and lung cancers. Our results identified USP36 as a crucial and bono fide deubiquitinating enzyme controlling c-Myc’s nucleolar degradation pathway. We are interested in further elucidating the deubiquitination regulation of c-Myc stability and oncogenic activity in cells and in vivo.
(3). 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.
(4). 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- and miR-130a-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
Sun X.-X., Dai M.-S. (2014) Deubiquitinating enzyme regulation of the p53 pathway: A lesson from Otub1. World J Biol Chem, 5(2): 75-84
Li Y., Challagundla K.B., Sun X.-X., Zhang Q., Dai M.-S. (2015) microRNA-130a associates with ribosomal protein L11 to suppress c-Myc expression in response to UV irradiation. Oncotarget, 6(2): 1101-1114
Sun X.-X., He X., Yin L., Komada M., Sears R.C., Dai M.-S. (2015) The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. Proc Nat Acad Sci USA , 112(12): 3734-3739
Sun X.-X., Sears R.C., Dai M.-S. (2015) Deubiquitinating c-Myc: USP36 steps up in the nucleolus. Cell Cycle, 14: in press