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

Projects:
Identification of a DNA damage activated signaling pathway through the Mismatch repair protein to c-Abl to p73, leading to the activation of apoptosis.  Defect in this apoptosis pathway accounts for the drug resistance of mismatch repair-deficient tumors.

Identification of a nuclear export signal in c-Abl, demonstrating those c-Abl shuttles between the cytoplasmic and nuclear compartments. 

Identification of a novel function for the retinoblastoma protein in the inhibition of DNA replication.  Identification of DNA damage-activated RB dephosphorylation in S-phase cells.  Demonstration that RB is required for an intra-S arrest in response to DNA damage.

Identification of a differentiation-programmed activation of p38 MAP kinase.  Identification of a defect in this pathway in human Rhabdomyosarcoma.  Demonstration that the enforced activation of p38 MAP kinase can rescue the differentiation defect of Rhabdomyosarcoma to induce terminal growth arrest.

Keywords: chronic myelogenous leukemia, retinoblastoma, tumor suppressor, oncogene, cell cycle, apoptosis, cell motility, DNA damage, drug resistance, signal transduction

Selected Publications:
Wang JYJ, F Ledley, S Goff, R Lee, Y Groner and D Baltimore. 1984). The mouse c-abl locus: molecular cloning and characterization. Cell 36:349-356.

Wang JYJ. (1985). Isolation of antibodies for phosphotyrosine by immunization with a v-abl oncogene-encoded protein. Mol. Cell. Biol. 5:3640-3643.

Morla AO and JYJ Wang. (1986). Protein tyrosine phosphorylation in the cell cycle of Balb/3T3 fibroblasts. Proc. Natl. Acad. Sci. USA 83:8191-8195.

Kipreos ET, GJ Lee and JYJ Wang. (1987). Isolation of temperature sensitive tyrosine kinase mutants of v-abl oncogene by screening with antibodies for phosphotyrosine. Proc. Natl. Acad. Sci. USA 84:1345-1349.

Morla AO, J Schreurs, A Miyajima and JYJ Wang. (1988). Hematopoietic growth factors activate the tyrosine phosphorylation of distinct sets of proteins in interleukin-3 dependent murine cell lines. Mol. Cell. Biol. 8:2214-2218.

Chan P-L, P Scully, J-Y Shew, JYJ Wang and W-H Lee. (1989). Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell 58:1193-1198.

Franz WM, P Berger and JYJ Wang. (1989). Deletion of an N-terminal regulatory domain of the c-abl tyrosine kinase activates its oncogenic potential. EMBO J. 8:137-147.

Morla AO, G Draetta, D Beach and JYJ Wang. (1989). Reversible tyrosine phosphorylation of cdc2; dephosphorylation accompanies activation during entry into mitosis. Cell 58:193-203.

Kipreos ET and JYJ Wang. (1990). Differential phosphorylation of c-Abl in cell cycle determined by cdc2 kinase and phosphatase activity. Science 248:217-220.

Lin BTY, S Gruenwald, W-H Lee and JYJ Wang. (1991). Retinoblastoma cancer suppressor gene product is a substrate of the cell cycle regulator cdc2 kinase. EMBO J. 10:857-864.

McWhirter JR and JYJ Wang. (1991). Activation of tyrosine kinase and microfilament-binding functions of C-Abl by BCR sequences in BCR/ABL fusion proteins. Mol. Cell. Biol. 11:1553-1565.

Kipreos ET and JYJ Wang. (1992). Cell cycle-regulated binding of c-Abl tyrosine kinase to DNA. Science 256:382-385.

Renshaw MW, ET Kipreos, MR Albrecht and JYJ Wang. (1992). Oncogenic v-Abl tyrosine kinase can inhibit or stimulate growth depending on the cell context. EMBO J. 11:3941-3951.

Baskaran R, ME Dahmus and JYJ Wang. (1993). Tyrosine phosphorylation of mammalian RNA polymerase II carboxylterminal domain. Proc. Natl. Acad. Sci. USA 90:11167-11171.

Welch PJ and JYJ Wang. (1993). A C-terminal protein binding domain in RB regulates the nuclear c-Abl tyrosine kinase in the cell cycle. Cell 75:779-790.

McWhirter JR, DL Galasso and JYJ Wang. (1993). A coiled-coil oligomerization domain of BCR is essential for the transforming function of BCR-ABL oncoproteins. Mol. Cell. Biol. 13:7587-7597.

Renshaw MW, JR McWhirter and JYJ Wang. (1995). The human leukemic oncogene bcr-abl abrogates the anchorage requirement but not the growth factor requirement for proliferation. Mol. Cell. Biol. 15:1286-93.

Welch PJ and JYJ Wang. (1995). Disruption of retinoblastoma protein function by coexpression of its C pocket fragment. Genes Dev. 9:31-46.

Knudsen ES and JYJ Wang. (1996). Differential regulation of retinoblastoma protein function by specific cdk phosphorylation sites. J. Biol. Chem. 271:8313-8320.

Liu Z-G, R Baskaran, E Lea-Chou, LD Wood, M Karin and JYJ Wang. (1996). Mouse fibroblasts exhibit three distinct signaling response to genotoxic stress. Nature 384:273-276.

Lewis LM, R Baskaran, S Taagepera, MA Schwartz and JYJ Wang. (1996). Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmic-nuclear transport. Proc. Natl. Acad. Sci. USA 93:15174-15179.

Tan X, SJ Martin, DR Green and JYJ Wang (1997). Degradation of retinoblastoma protein in tumor necrosis factor and CD95-induced cell death. J. Biol. Chem. 272:9613-9616.

Baskaran R, LD Wood, YLL Whitaker, CE Canman, SE Morgan, Y Xu, C Barlow, D Baltimore, A Wynshaw-Boris, MB Kastan and JYJ Wang. (1997). Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387:516-519.

Knudsen ES and JYJ Wang. (1997). Dual mechanisms for the inhibition of E2F binding by RB phosphorylation. Mol. Cell. Biol. 17: 5771-5783.

Puri PL, V Sartorelli, X-J Yang, Y Hamamori, L Kedes, JYJ Wang, A Graessmann, Y Nakatani and M Levrero. (1997) The acetyltransferase PCAF is essential for muscle differentiation. Mol. Cell 1: 35-45.

Whitaker LL, H Su, R Baskaran, ES Knudsen and JYJ Wang. (1998). Growth suppression by an E2F-binding defective retinoblastoma protein: contribution from the RB C-pocket. Mol. Cell. Biol. 18:4032-4042.

Knudsen ES, C Buckmaster, T-T Chen, JR Feramisco and JYJ Wang. (1998). Inhibition of DNA synthesis by RB: Effects on G1/S transition and S-phase progression. Genes & Dev. 12: 2278-2292.

Taagepera S, D McDonald, JE Loeb, LL Whitaker, AK MacLeod, JYJ Wang and TJ Hope. (1998). Nuclear-cytoplasmic shuttling of c-Abl tyrosine kinase. Proc. Natl. Acad. Sci. 95:7457-7462.

Gong J, A Costanzo, H-Q Yang, G Melino, WG Kaelin, M Levero and JYJ Wang. (1999). The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399: 806-809

Sartorelli V, PL Puri, Y Hamamori, V Ogryzko, G Chung, Y Nakatani, JYJ Wang and L Kedes.(1999). Acetylation of MyoD directed by PCAF is necessary for the execution of the muscle program. Mol.Cell 4:725-734.

Puri PL, Z Wu, P Zhang, LD Wood, K Bhakta, M Karin, J Han, J Feramisco and JYJ Wang. (2000). Induction of terminal differentiation by the constitutive activation of p38 MAP-kinase in human rhabdomyosarcom cells. Genes & Dev. 14: 574-584.

Chen T-T and JYJ Wang. (2000). Establishment of irreversible growth arrest in myogenic differentiation requires the RB LxCxE-binding function. Mol. Cell. Biol. 20: 5571-5580.

Knudsen KE, D Booth, S Naderi, Z Sever-Chroneos, AF Fribourg, IC Hunton, JR Feramisco, JYJ Wang and ES Knudsen. (2000). RB-dependent S-phase response to DNA damage. Mol. Cell. Biol. 20: 7751-7763.

Vigneri P and JYJ Wang. (2001). Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nature Med. 7: 228-234.

Puri PL, S Iezzi, P Stiegler, T-T Chen, RL Schiltz, GEO Muscat, A Giordano, L Kedes, JYJ Wang and V Sartorelli (2001). Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis. Mol. Cell 8: 885-897.

Woodring PJ, ED Litwack, DD O’Leary, GR Lucero, JYJ Wang and T Hunter (2002). Modulation of the F-actin cytoskeleton by c-Abl tyrosine kinase in cell spreading and neurite extension. J. Cell Biol. 156:879-892.

Naderi S, IC Hunton and JYJ Wang (2002). Radiation dose-dependent maintenance of G2 arrest requires retinoblastoma protein. Cell Cycle 1:193-200.

Chau BN, H Borges, T-T Chen, A Masselli, IC Hunton and JYJ Wang (2002). Signal dependent protection from apoptosis in mice with caspase-resistant RB. Nature Cell Biol. 4: 757-765.

Puri PL, K Bhakta, LD Wood, A Costanzo, J Zhu and JYJ Wang (2002). A myogenic differentiation checkpoint activated by genotoxic stress. Nature Genet. 32:585-593.

Shimodaira H, A Yoshioka-Yamashita, R Kolodner and JYJ Wang (2003). Interaction of mismatch repair protein PMS2 and the p53-related transcription factor p73 in apoptosis response to cisplatin. Proc. Natl. Acad. Sci. USA 100:2420-2425.

Chau BN and JYJ Wang (2003). Coordinated regulation of life and death by RB. Nature Rev. Cancer 3:130-138.

Woodring PJ, T Hunter and JYJ Wang (2003). Regulation of F-actin-dependent processes by the Abl family of tyrosine kinases. J. Cell Sci. 116:2613-2626.

Vella V, J Zhu, F Frasca, C-Y Li, P Vigneri, R Vigneri and JYJ Wang (2003). Exclusion of c-Abl from the nucleus restrains the p73 tumor suppression function. J. Biol. Chem. 278:25151-25157.

Truong T, G Sun, M Doorly, JYJ Wang and MA Schwartz (2003). Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl. Proc. Natl. Acad. Sci. USA 100:10281-10286.

Wang JYJ (2004). Controlling Abl: auto-inhibition and co-inhibition? Nature Cell Biol. 6: 3-7.

Borges HL, C Chao, Y Xu, R Linden and JYJ Wang (2004). Radiation-induced apoptosis in developing mouse retina exhibits dose-dependent requirement for ATM phosphorylation of p53. Cell Death and Diff. 11: 494-502.

Chau BN, TT Chen, YY Wan, J DeGregori and JYJ Wang (2004). Tumor necrosis factor alpha-induced apoptosis requires p73 and c-ABL activation downstream of RB degradation. Mol. Cell Biol. 24: 4438-4447.

Woodring PJ, J Meisenhelder, SA Johnson, G Zhou, J Field, K Shah, F Bladt, T Pawson, M Niki, PP Pandolfi, JYJ Wang and T Hunter (2004). c-Abl phosphorylates Dok1 to promote filopodia during cell spreading. J. Cell Biol. 165: 493-503.

Li, Chun-Ying, J Zhu, and JYJ Wang (2005). Ectopic expression of p73-alpha, but not p73-beta, suppresses myogenic differentiation. J. Biol. Chem., 280: 2159-2164.

Woodring PJ, T Hunter and JYJ Wang (2005). Mitotic phosphorylation rescues Abl from F-actin-mediated inhibition. J. Biol. Chem. 280: 10318-10335.

Borges H, J Bird, K Wasson, RD Cardiff, N Varki, L Eckmann and JYJ Wang (2005). Tumor promotion by caspase-resistant RB. Proc. Acad. Natl. Sci. USA, 102: 15587-15592.

Masselli A, JYJ Wang (2006). Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli. Oncogene 25:1290-1298.

Castro JE, CE Prada, RA Aguillon, S Kitada, T Fukada, M Moota, C Wu, F Dicker, G Sun, JYJ Wang, DA Carson, JC Reed and TJ Kipps (2006). Thymidine-phosphorothioate oligonucleotides induce activation and apoptosis of CLL cells independently of CpG motifs or BCL-2 gene interference. Leukemia 20:680-688.

Dicker F, AP Krater, CE Prada, T Fukuda, JE Castro, G Sun, JYJ Wang and TJ Kipps (2006). CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic Leukemia Cells lacking functional p53. Blood. 108:3450-7

Murray D, JYJ Wang and R Mirzayans (2006). DNA repair after low doses of ionizing radiation. International Journal of Low Radiation. 3:255-272.

Chao C, Z Wu, SJ Mazur, H Borges, M Rossi, T Lin JYJ Wang, CW Anderson, E Appella and Y Xu (2006). Acetylation of mouse p53 at lysine 317 negatively regulates p53 apoptotic activities after DNA damage. Mol Cell Biol, 26:6859-6869.

CB Nelson, CW Pan and JYJ Wang (2006) Separation of anti-proliferation and anti-apoptotic functions of retinoblastoma protein through targeted mutations of it’s A/B domain. PLoS ONE, Dec. Issue 1, e82, 8 pg.

Borges HL, I Hunton and JYJ Wang (2007). Reduction of apoptosis in Rb-Deficient embryos via Abl knockout. Oncogene. PMID 17173068.

Preyer M, C-W Shu, 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. In press.

Markey MP, J Bergseid, EE Bosco, K Stengel, H Xu, CN Mayhew, SJ Schwemberger, WA Braden, Y Jiang, G Babcock, AG Jegga, BJ Aronow, MF Reed, JYJ Wang and ES Knudsen. (2007). Loss of the retinoblastoma tumor suppressor: Differential action on transcriptional programs related to cell cycle control and immune function. Oncogene. In press.

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