Guan Chen, MD, PhD

Guan Chen, MD, PhDProfessor

(414) 955-8636 | Fax: (414) 955-6545


MD - Bengbu Medical College, Anhui, P.R. China - 1982
MS - Sun Yat-Sen Univeristy, Guangzhou P.R. China - 1985
PhD - Pharmacology, University of Heidelberg, Germany - 1990

Dr. Chen's Faculty Collaboration Database

Research Interest

Ras is the most established oncogene in human cancer, with its mutation (K-Ras) occurring in about 50% human colon cancer and its hyperexpression (H-Ras) in more than 50% of human breast cancer. Ras oncogene activity, however, is determined by downstream effectors and elucidation of this regulation is essential to understand why not all Ras mutations can lead to human malignancies. MAPKs (mitogen-activated protein kinases), including ERK, JNK, and p38, signal downstream of Ras by converting extracellular and Ras signals into specific cellular response through a group of transcription factors. Our previous work established that Ras-induced p38 alpha phosphorylation/activation inhibits the oncogene activity by negative feedback. Results from our recent studies further showed that p38 gamma, a p38 family protein, is induced by Ras and in turn required for Ras transformation in rat intestinal epithelial cells and for Ras-invasive activity in human breast cancer. These results together indicate that signaling integrations among p38 family members determine Ras oncogene activity in a given tissues and p38 proteins regulate Ras activity by isoform-dependent mechanisms. Currently, we are investigating mechanisms by which Ras induces p38 gamma expression and by which p38gamma is required for Ras-induced transformation / invasion.

Nuclear receptors are group of transcription factors that play an important role in reproduction, homeostasis, and cancer development through regulating gene expression in response to their ligand. Our second research interest is to study signal cross-talks between Ras/MAPK pathways and nuclear receptors. Studies from our lab have established a c-Jun/AP-1 dependent trans-activation for stress-induced vitamin D receptor (VDR) expression and an anti-apoptotic activity of VDR by a K-ras-dependent mechanism. Our results further showed that another nuclear receptor ER (estrogen receptor) inhibits stress MAPK-mediated cell death independent of its transcriptional activity by converting pro-apoptotic c-Jun activity into a c-Jun-dependent AP1 transcription. These results together suggest that nuclear receptors may cooperate with Ras/MAPKs to regulate stress-response independent of their transcription activity. We are currently investigating whether regulation of nuclear receptors represents a novel strategy for human cancer treatment.

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  Recent Publications

Yin, N., Qi, X., Tsai, S., Lu, Y., Basir, Z., Oshima, K., Thomas, J. P., Myers, C. R., Stoner, G., and Chen, G. (2016) p38g MAPK is required for inflammation-associated colon tumorigenesis. Oncogene, 35: 1039-1048 PMID: 25961922

Qi, X., Yin, N., Ma, S., Lepp, A., Tang, J., Jing, W., Johnson, B., Dwinell, MB., Chitambar, VR., Chen, G. (2015) p38g MAPK is a therapeutic target for triple-negative breast cancer by stimulation of cancer stem-like cell expansion. Stem Cells, 33:2738-2747 (PDF) PMID: 26077647

Ma, S., Yin, N., Qi, X., Pfister, S. L., Zhang, M., Ma, R., and Chen, G. (2015) Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER). Oncotarget, 6: 13320-13333, 2015 PMID: 26079946

Qi, XM, Xie, C., Hou, S., Li, G., Yin, N., Dong, L., Lepp, A., Chesnik, M. A., Mirza, S. P., Szabo, A., Tsai, S., Basir, Z., Wu, S., and Chen, G. Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer. Oncotarget 2014, 5: 4269-4282

Suresh P., Ma S., Migliaccio, A., and Chen, G.,  Protein-tyrosine phosphatase H1 (PTPH1) increases breast cancer sensitivity to anti-estrogens by dephosphorylating estrogen receptor (ER) at Tyr537. Mol Cancer Ther 13: 230-238, 2014

Hou, S., Padmanaban, S., Qi, X., Lepp, A., Mirza, S. P., and Chen, G. (2012) p38g MAPK signals through phosphorylating its phosphatase PTPH1 in regulating Ras oncogenesis and stress response. J Biol Chem, 287: 27895-27950 PMID:22730326

Yusuke Kobayashi*, Xiaomei Qi*, and Chen, G. (2012) MK2 regulates Ras oncogenesis through stimulating ROS production. Genes & Cancer, 3: 521-530 (*contributed equally) PMID:23264852 PMCID:3527985

Qi, X., Zhi, H., Lepp, A., Wang, P., Huang, J., Zainab Basir, Z., Chitambar, C., R., Chen, G. (2012) p38γ MAPK confers breast cancer hormone sensitivity by switching estrogen receptor (ER) signaling from the classical to non-classical pathway via stimulating ER phosphorylation and c-Jun transcription. J Bol Chem, 287: 14681-14691

Qi, X., Hou, S., Lepp, A., Li, R., Basir, Z., Lou, Z., Chen, G. (2011) Phosphorylation and stabilization of topoisomerase IIα by p38γ MAPK sensitize breast cancer cells to its poisons.  J. Biol. Chem, 286:35883-358901

Zhi, H., Hou, S., Li, R., Basir, Z., Xiang, Q., Szabo, A., Chen, G. (2011) PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization. Oncogene, 30: 1706-1715

Hou, S., Lepp, A., Chen, G. (2010) p38gamma MAP kinase (review).  UCSD-Nature Molecular Pages 1September 2010 / doi:10.1038/mp.a001720.01

Loesch, M., Ahi, H., Hou, S., Qi, X., Li, R., Basir, Z., Iftner, T., Cuenda, A., and Chen, G. p38Y MAPK cooperates Trans-activating Matrix Metalloproteinase 9. (2010), J. Biol. Chem. 2010, 185: 15149-15158

Hou, S., Zhi, H., Pohl, N., Loesch, M., Qi, X., Li, R., Basir, Z., and Chen, G. PTPH1 dephosphorylates and cooperate with p38Y MAPK to increase Ras oncogenesis through PDZ-mediated interaction. (2010), Cancer Res. 70: 2901-2910.

Loesch, M., Chen, G. (2008) The p38 MAPK stress pathway as a tumor suppressor or more? Frontiers in Bioscience, 13: 3581-3593.

Qi, X.M*., Pohl, N.M*., Loesch, M., Hou, S., Li, R., Qin, J. Z., Cuenda, A., and Chen, G. (2007) p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem 282: 31398-31408 (*contributed equally to the work).

Li, Q-P., Qi, X., Pramanik, R., Pohl, N. M., Loesch, M. and Chen, G. (2007) Stress-induced c-Jun-dependent vitamin D receptor (VDR) activation dissects the non-classical VDR pathway from the classical VDR activity. J. Biol. Chem., 282: 1544-1551 (LQ and QX contributed equally to this work).

Qi, X., Tang, J., Loesch, M., Pohl, N., Alkan, S. and Chen, G. (2006) p38γ mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion. Cancer Res., 66: 7540-7547

Tang, J., Qi, X., Mercola, D., Han, J., and Chen, G. (2005) Essential role of p38gamma in K-Ras transformation independent of phosphorylation. J. Biol. Chem. 280:23910-23917

Qi, X., Tang, J., Pramanik, R.,Schultz, R. M., Shirasawa, S., Sasazuki, T., Han, J., and Chen, G. (2004) p38 MAPK activation selectively induces cell death in K-ras mutated human colon cancer cells through regulation of vitamin D receptor.  J. Biol. Chem. 279: 22138-22144

Qi, X., Borowicz, S., Pramanik, R., Schultz, R. M., Han, J., and Chen, G. (2004) Estrogen receptor inhibits c-Jun-dependent stress-induced cell death by binding and modifying c-Jun activity in human breast cancer cells.  J. Biol. Chem. 279: 6769-6777

Pramanik, R., Qi, X., Borowicz , S., Choubey, D., Schultz , R. M., Han, J., and Chen, G. (2003) p38 isoforms have opposing effects on AP-1-dependent transcription through regulation of c-Jun: The determinant role of the isoforms in the p38 MAPK signal specificity. J. Biol. Chem.  278: 4831-4839

Qi, X., Pramanik, R., Wang, J., Schultz, R. M., Maitra, R. K., Han, J., DeLuca, H. F., and Chen, G. (2002) The p38 and JNK pathways cooperate to trans-activate vitamin D receptor via c-Jun/AP-1 and sensitize human breast cancer cells to vitamin D3-induced growth inhibition. J. Biol. Chem. 277: 25884-25892

Stacey, D., Hitomi, M., and Chen, G. (2000) The influence of cell cycle and oncogene activity upon topoisomerase IIalpha expression and drug toxicity.  Mol. Cell Biol. 20: 9127-9137

Chen, G., Hitomi, M., Han, J. and Stacey, D. W. (2000) Inhibition of Ras proliferative signaling by the p38 pathway via a negative feedback. J. Biol. Chem. 275: 38973-38980