MAPKs (mitogen-activated protein kinases), including ERK (extracellular signal-regulated kinase), JNK (c- Jun NH2-terminal kinase), and p38, are known to play a critical role in transduction and regulation of Ras oncogene activity by phosphorylation-dependent mechanisms. Our previous work demonstrated that Ras activates the p38 pathway, which in turn inhibits Ras proliferative activity by negative feedback. Here we propose that Ras activates p38gamma MARK by increasing its expression without stimulating its phosphorylation, and induced p38gamma is required for Ras transformation through a physical interaction with ERK proteins independent of phosphorylation. This activity of p38gamma contrasts with that of its family member p38alpha, which is activated by Ras through phosphorylation, leading to an inhibition of Ras transformation. This hypothesis is based on our preliminary studies showing that K-Ras induces p38gamma protein expression but inhibits its phosphorylation, and that depletion of induced p38gamma suppresses K-Ras transformation in rat intestinal epithelial IEC-6 cells. Furthermore, gene arrays showed that p38gamma transcripts are increased in a set of primary human colon cancers than in matched normal tissues. The following specific aims will test this hypothesis: I) To demonstrate that p38gamma acts downstream of the MEK/ERK pathway to promote Ras transformation independent of phosphorylation;II) To determine whether p38gamma is required for Ras transformation through a complex formation with ERK proteins;III) To investigate if p38gamma is up-regulated in K-Ras mutated human colon cancer and required for K-Ras-dependent malignant growth in vitro and in mice. This study will demonstrate a novel function of stress p38gamma MARK as a Ras effector through induced expression independent of phosphorylation and thereby reveal a mechanism by which Ras oncogene activity is determined by a signaling integration between anti-oncogenic p38alpha and pro-oncogenic p38gamma. Information obtained will directly contribute to human colon cancer prevention and treatment by demonstrating the diagnostic value of increased p38gamma expression and the therapeutic significance of p38gamma depletion.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA091576-11
Application #
7752497
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2000-09-13
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
11
Fiscal Year
2010
Total Cost
$223,970
Indirect Cost
Name
Medical College of Wisconsin
Department
Pharmacology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Hou, Songwang; Suresh, Padmanaban S; Qi, Xiaomei et al. (2012) p38? Mitogen-activated protein kinase signals through phosphorylating its phosphatase PTPH1 in regulating ras protein oncogenesis and stress response. J Biol Chem 287:27895-905
Zhi, H-Y; Hou, S-W; Li, R-S et al. (2011) PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization. Oncogene 30:1706-15
Hou, Song-Wang; Zhi, Hui-Ying; Pohl, Nicole et al. (2010) PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction. Cancer Res 70:2901-10
Loesch, Mathew; Zhi, Hui-Ying; Hou, Song-Wang et al. (2010) p38gamma MAPK cooperates with c-Jun in trans-activating matrix metalloproteinase 9. J Biol Chem 285:15149-58
Loesch, Mathew; Chen, Guan (2008) The p38 MAPK stress pathway as a tumor suppressor or more? Front Biosci 13:3581-93
Qi, Xiaomei; Pohl, Nicole M; Loesch, Mathew et al. (2007) p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem 282:31398-408
Li, Qing-Ping; Qi, Xiaomei; Pramanik, Rocky et al. (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 282:1544-51
Qi, Xiaomei; Tang, Jun; Loesch, Mathew et al. (2006) p38gamma mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion. Cancer Res 66:7540-7
Qi, Xiaomei; Borowicz, Stanley; Pramanik, Rocky et al. (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 279:6769-77
Qi, Xiaomei; Tang, Jun; Pramanik, Rocky et al. (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 279:22138-44

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