Guan Chen, MD, PhD

Professor

Contact Information

Biography

General Interests

Cancer Research

Education

1982, Bengbu Medical College, MD
1985, Sun Yat-Sen University, MS
1990, University of Heidelberg, Germany, PhD

Research Interests

Dr. Chen's Faculty Collaboration Database

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.

Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).

(Ma S, Yin N, Qi X, Pfister SL, Zhang MJ, Ma R, Chen G.) Oncotarget. 2015 May 30;6(15):13320-33.
p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion.

(Qi X, Yin N, Ma S, Lepp A, Tang J, Jing W, Johnson B, Dwinell MB, Chitambar CR, Chen G.) Stem Cells. 2015 Sep;33(9):2738-47.
p38γ MAPK is required for inflammation-associated colon tumorigenesis.

(Yin N, Qi X, Tsai S, Lu Y, Basir Z, Oshima K, Thomas JP, Myers CR, Stoner G, Chen G.) Oncogene. 2016 Feb 25;35(8):1039-48.
Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer.

(Qi X, Xie C, Hou S, Li G, Yin N, Dong L, Lepp A, Chesnik MA, Mirza SP, Szabo A, Tsai S, Basir Z, Wu S, Chen G.) Oncotarget. 2014 Jun 30;5(12):4269-82.
Protein-tyrosine phosphatase H1 increases breast cancer sensitivity to antiestrogens by dephosphorylating estrogen receptor at Tyr537.

(Suresh PS, Ma S, Migliaccio A, Chen G.) Mol Cancer Ther. 2014 Jan;13(1):230-8.
MK2 Regulates Ras Oncogenesis through Stimulating ROS Production.

(Kobayashi Y, Qi X, Chen G.) Genes Cancer. 2012 Jul;3(7-8):521-30.
p38γ Mitogen-activated protein kinase signals through phosphorylating its phosphatase PTPH1 in regulating ras protein oncogenesis and stress response.

(Hou S, Suresh PS, Qi X, Lepp A, Mirza SP, Chen G.) J Biol Chem. 2012 Aug 10;287(33):27895-905.
p38γ mitogen-activated protein kinase (MAPK) confers breast cancer hormone sensitivity by switching estrogen receptor (ER) signaling from classical to nonclassical pathway via stimulating ER phosphorylation and c-Jun transcription.

(Qi X, Zhi H, Lepp A, Wang P, Huang J, Basir Z, Chitambar CR, Myers CR, Chen G.) J Biol Chem. 2012 Apr 27;287(18):14681-91.
Phosphorylation and stabilization of topoisomerase IIα protein by p38γ mitogen-activated protein kinase sensitize breast cancer cells to its poisons.

(Qi X, Hou S, Lepp A, Li R, Basir Z, Lou Z, Chen G.) J Biol Chem. 2011 Oct 14;286(41):35883-90.
PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization.

(Zhi HY, Hou SW, Li RS, Basir Z, Xiang Q, Szabo A, Chen G.) Oncogene. 2011 Apr 07;30(14):1706-15.
PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction.

(Hou SW, Zhi HY, Pohl N, Loesch M, Qi XM, Li RS, Basir Z, Chen G.) Cancer Res. 2010 Apr 01;70(7):2901-10.
p38gamma MAPK cooperates with c-Jun in trans-activating matrix metalloproteinase 9.

(Loesch M, Zhi HY, Hou SW, Qi XM, Li RS, Basir Z, Iftner T, Cuenda A, Chen G.) J Biol Chem. 2010 May 14;285(20):15149-58.

Chen Guan MD PhD