Mu-Shui Dai, M.D., Ph.D
Mu-Shui Dai, M.D., Ph.D. - Assistant Professor
Oregon Health & Science University
3181 SW Sam Jackson Park Road
Mail Code # L103A
Portland, OR 97239
Office: 503 494-9917
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.
The tumor suppressor p53 gene is mutated or deleted in more than half of all human cancers and the rest of cancers often retain malfunctions in the p53 regulatory pathways, including mutations of tumor suppressor Arf and overexpression of proto-oncogene MDM2. p53 is controlled by MDM2, an ubiquitin E3 ligase, via a feedback mechanism. While the MDM2-p53 feedback loop and its regulation in response to various stresses have been extensively studies, we have recently revealed a critical role for several ribosomal proteins (L5, L11, L23, and S27a) in p53 activation in response to ribosomal stress (also called nucleolar stress) induced by perturbation of ribosomal biogenesis, via inhibiting MDM2. Interestingly, genetic alterations of several ribosomal proteins, including S19, S27a, S14, L5 and L11, are found in patients with Diamond-Blackfan Anemia (DBA) and several other forms of anemia syndromes with increased cancer susceptibility. Currently it is not known why and how multiple ribosomal proteins are involved in regulating the MDM2-p53 loop and whether some ribosomal proteins are haploinsufficiency tumor suppressors. We will try to address these questions by characterizing the mechanisms underlying ribosomal protein regulation of the MDM2-p53 feedback loop.
We are also interested in studying the regulation 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 an 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.
Interestingly, we have found that ribosomal protein L11 not only directly inhibits c-Myc transactivation activity, but also regulates c-myc mRNA stability. L11 control 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 using molecular, biochemical, and proteomic methods.
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
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., 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
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
Dai M.-S., Sun X.-X., Lu H. (2010) Ribosomal protein L11 associates with c-Myc at 5S rRNA and tRNA genes and regulates their expression. J Biol Chem, 285(17): 12578-12594