Yanping Zhang

Yanping Zhang


Department of Radiation Oncology and Lineberger Comprehensive Cancer Center

Ph.D., Molecular Biology
University of Nebraska, Lincoln

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Department of Radiation Oncology
Zhang Lab Website

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Research Interests

  • Genetics and molecular mechanisms of cancer

Research Synopsis

The ribosomal protein-Mdm2-p53 pathway and energy metabolism

Cellular growth and division are two fundamental processes that are exquisitely sensitive and responsive to environmental fluctuations. One of the most energetically demanding functions of these processes is ribosome biogenesis, the key component to regulating overall protein synthesis and cell growth. Perturbations to ribosome biogenesis have been demonstrated to induce an acute stress response leading to p53 activation through the inhibition of Mdm2 by a number of ribosomal proteins (RPs). The energy status of a cell is a highly dynamic variable that naturally contributes to metabolic fluctuations, which can impact both the rates of ribosome biogenesis and p53 function. This, in turn, determines whether a cell is in an anabolic, growth promoting state or a catabolic, growth suppressing state.

Our previous studies have shown that inhibition of ribosomal biogenesis can activate p53 through RP-mediated suppression of Mdm2 E3 ligase activity. To study the RP-Mdm2-p53 pathway, we generated mice carrying a single cysteine-to-phenylalanine substitution in the central zinc finger of Mdm2 (Mdm2C305F), disrupting Mdm2’s binding to RPL11 and RPL5 [Cancer Cell]. Despite developmentally normal and maintaining an intact p53 response to DNA damage the Mdm2C305F mice demonstrate a diminished p53 response to perturbations in ribosomal biogenesis.

Recently, our studies further indicate that the RP-Mdm2-p53 pathway is in fact an essential sensor of nutrient stress and regulator of energy output. Our results demonstrate, for the first time in an animal model, that p53 is indeed critically involved in regulating metabolism. Recent study using the Mdm2C305F mouse model further demonstrate that the RP-Mdm2-p53 pathway regulates glucose tolerance and energy homeostasis, and suggests that functional modulation of this pathway might have significant effect on both development and treatment of obesity and diabetes.

In vivo
function of Mdm2 E3 ubiquitin ligase and the role of Mdm2-MdmX interaction in p53 regulation

The tumor suppressor p53 is a critical mediator of the cellular stress response, maintaining genomic integrity and preventing oncogenic transformation by inducing both cell cycle arrest and apoptotic cell death. Mdm2, the primary negative regulator for p53, is believed to control p53 through binding to and suppressing the transactivation activity of p53 and functioning as an E3 ubiquitin ligase targeting p53 for proteosomal degradation. MdmX, an Mdm2 homologue, is believed to suppress p53 through binding in a similar mechanism to Mdm2; but MdmX lacks E3 ubiquitin ligase activity. Both Mdm2 and MdmX knockout mice are embryonically lethal and can be rescued with concomitant deletion of p53, indicating both are critical in p53 regulation. However, despite intensive study, it is still incompletely understood why it requires Mdm2 andMdmX for p53 regulation and how Mdm2 and MdmX cooperatively regulate p53. We have previously developed Mdm2C462A knock-in mice in which the Mdm2C462A mutant lacks E3 ligase activity [Cancer Cell]. Interestingly, although the Mdm2C462A protein is capable of binding to p53, the knock-in mice demonstrate early embryonic lethality, which can be rescued by simultaneous deletion of p53, indicating that Mdm2-p53 binding alone, in the absence of Mdm2-mediated ubiquitination, is insufficient for p53 control.

However, along with inactivating Mdm2 E3 ligase, the Mdm2C462A mutation also disrupts Mdm2-MdmX binding, and in vitro studies have shown that the Mdm2-MdmX interaction amplifies Mdm2 E3 ligase activity towards p53. To distinguish which of the changes—disrupting the E3 activity or the Mdm2-MdmX binding, is causing the lethality, we have generated another knock-in mice expressing Mdm2Y487A, which lacks E3 activity but maintains the ability to bind to p53 and MdmX. The mouse model would likely provide novel conceptual insight into the function and mechanism of Mdm2-MdmX co-regulation of p53.

Mitochondrial p32 regulation of the p53 tumor suppression signaling pathway and apoptotic cell death

Apoptosis is a tightly regulated form of programmed cell death that is critical for proper embryonic development, tissue homeostasis, and immune response, and aberrant regulation of this process contributes to autoimmune disorders, neurodegenerative disease, and cancer. A mitochondria-localized protein, p32, was recently identified by our lab as a binding partner for the tumor suppressor p14ARF [Cancer Cell]. Our data have shown that p32 is essential for p14ARF to localize to mitochondria and to induce p53-dependent apoptosis; cancer derived p14ARF mutations that disrupt p32 binding can undermine p14ARF’s pro-apoptotic function. Recently, we found that p32 is in fact essential for apoptosis induced by a variety of apoptotic stimuli, including DNA damaging and non-DNA damaging stressors, indicating that p32 is a general pro-apoptosis factor.

Our preliminary studies have showed that p32 exerts its pro-apoptotic activity downstream of mitochondrial events of apoptosis, such as mitochondrial outer membrane permeabilization (MOMP) and release of cytochrome c, and suggested that p32-induced apoptosis takes place by a mechanism that is independent of cytochrome c. Using a combination of biochemical, cellular, and genetic approaches we want to determine the biological function and molecular mechanism of p32 regulation of apoptosis. It has been recently shown that p32 plays a role in regulating the balance between glycolysis and oxidative phosphorylation. Thus, we want to investigate whether p32 at one hand contributes to day-to-day mitochondrial metabolic activities and on the other hand promotes apoptotic cell death when non-repairable mitochondrial damage occurs.



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Contact Information

Office Location:
31-321 LCCC

Mailing Address:
CB # 4262
UNC-CH School of Medicine
Chapel Hill, NC 27599-4262

Office Phone: 919-966-7713 / 919-445-5287
Lab Phone: 919-843-6534
Fax: 919-966-7681



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