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REGULATION OF RAS ACTIVITY BY THE P38 PATHWAY

Award Number: R01CA091576
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2000
PERIOD OF PERFORMANCE END DATE: 12/31/2010

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REGULATION OF RAS ACTIVITY BY THE P38 PATHWAY - DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2010 ( Subtotal = $223,970 )
2010	2010	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	001	11	1/26/2010	NON-COMPETING CONTINUATION	$22,396
2010	2010	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	11	12/31/2009	NON-COMPETING CONTINUATION	$201,574
														Subtotal = $223,970

Issue Date FY: 2009 ( Subtotal = $223,970 )
2009	2009	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	10	12/18/2008	NON-COMPETING CONTINUATION	$201,574
2009	2009	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	001	10	3/17/2009	NON-COMPETING CONTINUATION	$22,396
														Subtotal = $223,970

Issue Date FY: 2008 ( Subtotal = $223,970 )
2008	2008	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	9	12/21/2007	NON-COMPETING CONTINUATION	$223,970
														Subtotal = $223,970

Issue Date FY: 2007 ( Subtotal = $223,970 )
2007	2007	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	8	1/9/2007	NON-COMPETING CONTINUATION	$223,970
														Subtotal = $223,970

Issue Date FY: 2006 ( Subtotal = $230,659 )
2006	2006	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	7	8/15/2006	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$174,882
2006	2006	LOYOLA UNIVERSITY MEDICAL CENTER	820 N MICHIGAN AVENUE	CHICAGO	IL	60611	COOK	USA	Cancer Biology Research	000	6	12/29/2005	COMPETING CONTINUATION	$55,777
														Subtotal = $230,659

Issue Date FY: 2004 ( Subtotal = $216,600 )
2004	2004	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cancer Biology Research	000	5	7/27/2004	NON-COMPETING CONTINUATION	$216,600
														Subtotal = $216,600

Issue Date FY: 2003 ( Subtotal = $216,600 )
2003	2003	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cancer Biology Research	000	4	8/29/2003	NON-COMPETING CONTINUATION	$216,600
														Subtotal = $216,600

Issue Date FY: 2002 ( Subtotal = $216,600 )
2002	2002	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cancer Biology Research	000	3	8/12/2002	NON-COMPETING CONTINUATION	$216,600
														Subtotal = $216,600

Issue Date FY: 2001 ( Subtotal = $216,600 )
2001	2001	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cancer Biology Research	000	2	8/6/2001	NON-COMPETING CONTINUATION	$216,600
														Subtotal = $216,600

Issue Date FY: 2000 ( Subtotal = $214,130 )
2000	2000	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cancer Biology Research	000	1	9/13/2000	NEW	$214,130
														Subtotal = $214,130

Grand Total All Awards = $2,207,069

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REGULATION OF RAS ACTIVITY BY THE P38 PATHWAY

Award Number: R01CA091576

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/13/2000

PERIOD OF PERFORMANCE END DATE: 12/31/2010

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