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 p38alpha phosphorylation/activation inhibits the oncogene activity by negative feedback. Results from our recent studies further showed that p38gamma, 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 p38gamma 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.
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.