Yiwei Zhang, PhD

My scientific interests focus on the molecular dissection and translational research of the p53 family (including MDM2/MDMX-p53 pathway and its targets, p63 and its targets) in controlling cell metabolism, growth and death, organogenesis, and the relationship between metabolic homeostasis and tumorigenesis, using cell culture system and animal models.

In my previous research, through cell-culture based experiments I have found that metabolic stresses (such as glucose deprivation and anti-diabetes drug treatment) can activate p53 through AMPK-mediated phosphorylation of MDMX, and subsequent binding of p-MDMX to 14-3-3 and dissociation of MDMX with p53. To further understand the physiological and pathological significance of this pathway in metabolism and tumorigenesis, I have recently recruited MDMX3SA/3SA knock-in mouse line that contains 3 point mutations of phosphorylation sites in Mdmx gene, and MDMX3SA/3SA; MDM2C305F/C305F (which contains a point mutation to disable the ribosomal stress caused binding of MDM2 to RPL11/L5) double knock-in (DKI) mouse line. My recent results indicate that DKI mice on normal chow diet exhibit mild, but significant, metabolism abnormalities, which is exacerbated by high-fat-diet feeding. Consistently, MEFs isolated from DKI mice possess higher capacity of differentiation into adipocytes, and less beige fat is induced in the subcutaneous white adipose tissue of DKI mice after chronic cold exposure. Furthermore, I observe that the survival rate of DKI mice is significantly lower compared to either control or single knock-in groups, which may be due to the higher morbidity of cancers in DKI mice. Because of these observations, in the near future I will further specifically investigate if dual defects of these p53 activation pathways will accelerate hepatocellular carcinogenesis (HCC) or not, using DEN-induced HCC mouse model and syngeneic mouse tumor model. By employing MDM2 and MDMX conditional knockout mouse lines my previous study has also verified that MDM2 and MDMX separately or corporately regulate p53, more than forming a complex, during different organogenesis and related disease progress, suggesting different targets of MDM2/MDMX-p53 pathway may be involved in different organ development and disease progress. To identify these targets of p53 and dissect their functions in different cellular events, organogenesis and diseases is also my current project. My colleague has identified CCDC3 as a transcriptional target of p63, a member of p53 family, and found that CCDC3 may take partial responsibility for p63-mediated lipid metabolism and adipogenesis, by recruiting cell culture system. Recently I have created Ccdc3-knockout mouse line to investigate the roe of CCDC3 in metabolic homeostasis and potential tumorigenesis in vivo. Finally, I have demonstrated that INZ (a small molecule identified by my colleague specifically targeting p53 pathway) can sensitize cancer cells to cisplatin, doxorubicin and Nutlin-3. Furthermore, I have assisted the lab in applying grants including RO1, R35 and R21 during the past years, and acquired a lot of experience in grant writing, such as strategy description, experimental design, data organization, and so on. Hence, I am experienced in cellular and molecular biology, biochemistry, pharmacology, developmental biology and genetics.