Our Science – Zhang Website
Shuling Zhang, M.D., Ph.D.
Our current research is focused on the functions of p16INK4a and mTOR in the development of plasma cell tumors. Mouse plasmacytoma susceptibility provides a model for the dissection of complex genetic traits associated with cancer. BALB/c mice are susceptible to the development of pristane-induced plasma cell tumors, while DBA/2 and C57BL/6 strains are genetically resistant to the plasmacytomagenic effects of pristane. Results from backcross and intercross experiments showed that several Pctr loci are involved in this model system of human B-cell neoplasia. Two of these genes (Pctr1 and 2) reside in noncontiguous, nonoverlapping segments of the distal half of mouse Chr 4. One of the BALB/c susceptibility and modifier loci, Pctr1, was mapped to a 1.5-centimorgan (cM) chromosomal region that includes Cdkn2a, which encodes p16INK4a and p19ARF, and was found to be polymorphic between BALB/c and DBA/2 in the promoter and coding regions. The knockout mice for the Cdkn2a locus develop accelerated plasmacytomagenesis. Both p16INK4a and p19ARF are tumor suppressors involved in regulating cell cycle checkpoints and apoptosis. When tested with wild-type (DBA/2) p16INK4a, the BALB/c-specific variant of p16INK4a was inefficient in its ability to inhibit the activity of cyclin D2/CDK4 in kinase assays, to induce growth arrest of mouse plasmacytoma cell lines in cell cycle analyses, and to prevent ras-induced transformation of NIH 3T3 cells in ras transformation assays. We also found that RREB, a ras-responsive transcriptional element with zinc-finger binding motifs, can repress p16INK4a expression, and the BALB/c promoter is more sensitive to regulation by RREB than DBA/2 promoter.
Other of candidate genes, Pctr2, was identified by positional cloning, as the serine-threonine protein kinase FKBP-1-rapamycin associated protein (FRAP [FKBP12-rapamycin-associated protein], also called mTOR). mTOR promoter and coding regions were also found to be polymorphic between BALB/c and DBA/2 mice. mTOR is a key component of a signaling pathway that integrates inputs from nutrients and growth factors to regulate cell growth. Our previous studies have shown that mTOR is a candidate tumor susceptibility gene for mouse plasmacytoma development; the kinase activity of tumor susceptible BALB/c mice was much lower than that of the tumor resistant DBA/2 mouse.
1. Studying the contribution of p16INK4a and mTOR in development of plasma cell tumors in vivo by using conditional knock-in/out techniques.
2. Studying the transcriptional regulation of mTOR in mouse plasma cell tumors.
3. Studying the role of RREB on the transcriptional regulation of p16INK4a in mouse plasma cell tumors by using siRNA, lentivirus-shRNA, ChIP, and Gel Shift techniques.
4. Investigating the effect of methylation on the development of mouse plasma cell tumors.
This page was last updated on 3/5/2013.