Yue Xiong, PhD

• Xiong Lab Website
• Publication List

RESEARCH INTERESTS:

Mammalian Cell Cycle Control and Tumor Suppression

Inevitably, the molecular pathways controlling cell growth must interact with those regulating cell division. An alteration in this critical interaction may be the cause of human cancer, which is characterized by deregulated cell growth and division. The major goal of this laboratory is to understand the mechanism(s) controlling cell cycle progression in normal human cells, and how this control is altered during tumorigenesis. Three major areas of our current research are described below with representative publications.

CDK inhibitors in tumor suppression and stem cell control

Eukaryotic cell cycle progression is primarily controlled by a family of protein serine/threonine kinases, known as cyclin-dependent kinases (CDKs), that consist of an activating cyclin subunit and a catalytic subunit CDK. The principle negative regulation of CDKs is provided by two families of CDK inhibitors which link cell cycle control to such diverse processes as DNA repair, terminal differentiation, tumor suppression, cell senescence and stem cell expansion. We are taking a genetic approach toward these issues by targeting specific CDK inhibitor genes (knock-out) in mice to determine their in vivo function. Our current research is focused on determining the mechanism underlying the function of CDK inhibitor genes in stem cell control and tumor suppression.

Regulation of INK4a and ARF gene expression 

Through utilizing different promoters and alternative reading frames, the mammalian ARF-INK4a locus uniquely encodes two unrelated proteins, ARF and p16INK4a, which both function in cell cycle control and tumor suppression. The ARF-INK4a locus is frequently altered in human cancer, with an estimated frequency second only to p53 mutations. INK4a maintains the retinoblastoma (Rb) family proteins in their growth suppressive state through inhibition of cyclin D-dependent kinases 4 and 6 (CDK4 and CDK6) activity, while ARF binds to MDM2 and prevents MDM2-mediated p53 degradation, thereby activating p53. The signals and mechanisms regulating the INK4a and ARF gene expression, however, remain poorly understood. Our current research in this area is focused on elucidating the biochemical mechanisms leading to the activation and silencing of INK4a and ARF gene expression through histone modification.

Cullin-RING family E3 ubiquitin ligases

Most cellular processes, including notably cell cycle control and tumor suppression, are regulated in large part by the ubiquitin-mediated modification and degradation of key regulatory proteins such as cyclins, CDK inhibitors, E2F transcription factors and the p53 tumor suppressor. The mechanisms targeting specific proteins for ubiquitination, in most cases, are poorly understood. We previously discovered two novel RING finger proteins in mammalian cells, ROC1 and ROC2 (for RING of cullins), which constitute active ubiquitin ligases with members of the cullin family. We have also discovered that Cullins 3 and 4 could assemble in vivo as many as 200 and 100 distinct E3 ubiquitin ligases through interacting with a conserved protein motif, the BTB domain and WD40 repeats, respectively. Taking combined genetic, biochemical and proteomic approaches, our current research in this area is focused on the systematic identification and functional characterization of cullin-RING family E3 ligases.

For more information, please visit our web page at: http://cancer.med.unc.edu/xionglab/webpage/webpage.html.

RECENT PUBLICATIONS: