Research / Clinical Summary

Jean Wang, PhD Professor, Medicine / Biological Sciences Cancer Biology Program Contact by Email Visit the Website

Other Leadership Roles:
Associate Director for Basic Research

Lab location: Moores Cancer Center, Room 4114
Office phone: 822-2001; Lab phone: 534-2828; Email: jywang@ucsd.edu

Lab composition: 1 Clinical Assistant Professor, 1 Project Scientist, 7 Postdocs, 1 Graduate Student, 1 Technician and 2 Undergraduate Research Students.

Research Interests: Cancer genes in the regulation of cell death. Our research is focused on biological mechanisms that regulate the cellular decision to commit suicide in response to chemotherapeutic drugs and inflammatory stress. My laboratory employs biochemistry, cell biology, molecular biology, mouse genetic models and high throughput technologies to interrogate the functional links among several cancer genes in the regulation of cell death.

Current Projects: Our current research is focused on how the ABL tyrosine kinase and the Retinoblastoma tumor suppressor (RB) regulate cell death induced by cytotoxic drugs and tumor necrosis factor. We also study the mechanisms underlying the resistance of leukemic stem cells to anti-oncogene drugs.

DNA damage-induced apoptosis: Regulation of DNA damage-induced apoptosis is important to oncology in two ways. Firstly, the majority of carcinogens are genotoxins that cause DNA damage and that the apoptotic response to carcinogens is an important tumor suppression mechanism. Secondly, a number of mainstay cancer therapeutic agents are genotoxins and their efficacies can be influenced by the status of DNA damage-induced apoptosis in tumor cells.

The ubiquitously expressed ABL tyrosine kinase is activated by DNA damage to regulate DNA repair and gene expression that results in the stimulation of apoptosis. At the mechanistic level, we are currently focused on how ABL-dependent tyrosine phosphorylation of the RNA polymerease II-C-terminal repeated domain (CTD) regulates the co-transcriptional processing of nascent RNA, including the regulation of alternative splicing as well as the processing of pri-microRNA to generate pre-microRNA. At the physiological levels, we have constructed specific mutant alleles in the mouse Abl gene and are using these mice to interrogate the role of ABL in the response of tumors as well as normal tissues, e.g., the kidney, to genotoxic stress induced by chemotherapeutic drugs.

Tumor necrosis-factor-induced apoptosis: Tumor necrosis factor (TNF) is a major inflammatory cytokine that orchestrates the systemic responses to infections and injuries. TNF binds to and stimulates its ubiquitously expressed type-1 receptor (TNFRI) to activate NF-kB, JNK or caspase-8, leading to the stimulation of inflammation/survival, necrosis and apoptosis, respectively. The rules that govern which of the three responses predominate upon TNF exposure are not understood. However, in the context of inflammation-associated carcinogenesis, TNF-induced NF-kB activation plays a role in tumor promotion.

We have demonstrated that the RB protein is a substrate of caspase and undergoes caspase-8-dependent cleavage at a C-terminal site in TNF-treated cells. We have created in the mouse genome an Rb-MI allele that encodes a caspase-resistant RB protein and shown that the intestinal epithelial cells in the Rb-MI mice are resistant to TNF-induced death. This apoptosis resistance is associated with the spontaneous development of intestinal tumors in mice where the Rb-MI allele is combined with the loss of p53. Mechanistically, we are testing the hypothesis that cleavage of RB is required for the sustained activation of caspase-8 so that Bid can be cleaved to promote TNF-induced apoptosis. At the physiological level, we are analyzing the role of Rb-MI in inflammation-associated development of colonic and bladder cancers in the mice.

Innate resistance of BCR-ABL transformed leukemic stem cells to imatinib. BCR-ABL is an oncogenic tyrosine kinase encoded by the abnormal Philadelphia chromosome found in human CML patients. Imatinib is a small molecule drug that binds to and inhibits the BCR-ABL kinase. Prior to the development of imatinib, CML was an incurable disease. Since the approval of imatinib, CML has become a chronic disease that is efficiently controlled by the daily oral intake of this kinase inhibitor. Unfortunately, imatinib does not kill the CML stem cells, as a result, CML patients have to take the pill continuously and risk the development of drug-resistance. We have developed a mouse model for the CML stem cells and shown that these cells are not killed by imatinib despite the fact that the drug does inhibit the BCR-ABL kinase in these stem cells. We have demonstrated that the CML stem cells do not become addicted to the BCR-ABL kinase, however, the leukemic progenies from these cells develop addiction and are thus highly sensitive to imatinib. These results suggest that oncogene addiction is a developmentally regulated trait. We are conducting experiments to understand how CML stem cells resist the addictive effects of the BCR-ABL oncogene.

Recent representative publications:

Borges HL, I Hunton and JYJ Wang (2007). Reduction of apoptosis in Rb-deficient embryos via Abl knockout. Oncogene 26:3868-3877.

Preyer M, C-W Shu, and JYJ Wang. (2007). Delayed activation of BAX by DNA damage in embryonic stem cells with knock-in mutations of Abl nuclear localization signals. Cell Death and Diff 14:1139-1148.

Huang X-D, A Masselli, IC Hunton, S Frisch, Y Jiang and JYJ Wang. (2007). Blockade of TNF-induced Bid cleavage by caspase-resistant Rb. J. Biol. Chem 282:29401-29413.

Jin H, and JYJ Wang (2007). Abl tyrosine kinase promotes dorsal ruffles but restrains lammellipodia extension during cell spreading on fibronectin. Mol. Biol. Cell 18:4143-4154.

Kim U, C-W Shu, KY Dane, PS Daugherty, JYJ Wang, and HT Soh (2007). Selection of mammalian cells based on their cell-cycle phase using dielectrophoresis. Proc. Natl. Acad. Sci. USA 104:20708-20712.

Huang X-D, JYJ Wang, and X Lu (2008). Systems analysis of quantitative shRNA-library screens identifies novel regulators of cell adhesion. BMC Systems Biology 2:49.

Huang X-D, D Wu, H Jin, DG Stupack, and JYJ Wang (2008). Induction of cell retraction by the combined actions of Abl-CrkII and Rho-ROCK1 signaling. Journal of Cell Biology 183:711-723.

Marinovic-Terzic I, A Yoshioka-Yamashita, H Shimodaira, E Avedievich, IC Hunton, RD Kolodner, W Edelmann and JYJ Wang (2008). Apoptotic function of human PMS2 compromised by the nonsynonymous single nucleotide polymorphic variant R20Q. Proc. Natl. Acad. Sci. USA 105:13993-13998.

Minami Y, SA Stuart, T Ikawa, A Banno, Y Jiang, IC Hunton, D Young, C Murre, C Jamieson, and JYJ Wang (2008). BCR-ABL-transformed GMP as myeloid leukemic stem cells. Proc. Natl. Acad. Sci. USA 105:17967-17972.

Stuart, SA and JYJ Wang (2009). Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells. J. Biol. Chem 284:15061-15070.

Huang V, X Lu, Y Jiang, and JYJ Wang (2009). Effect of hydorxyurea on the promoter occupancy profiles of p53 and p73. BMC Biol 7:35.