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PROTEIN STRUCTURE AND ONCOGENESIS

Award Number: R01CA042500
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/1988
PERIOD OF PERFORMANCE END DATE: 06/30/2005

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PROTEIN STRUCTURE AND ONCOGENESIS - DESCRIPTION: (PROVIDED BY APPLICANT) The ras oncogene-encoded p21 protein, vital in control of the cell cycle, becomes oncogenic when single amino acid substitutions (like Val-for-Gly 12) occur at critical positions in the polypeptide chain. Oncogenic, unlike normal, p21 causes cell transformation, maturation (meiosis) of Xenopus laevis oocytes and many human malignancies, making it important to devise ways to block its effects. Computer-based molecular modeling studies suggest that oncogenic amino acid substitutions cause changes in the conformation of domains of the protein. Synthetic peptides corresponding to three of these domains (35-47, 96-110 and 115-126) block oncogenic p21- but not insulin-activated normal p21-induced oocyte maturation. Val l2-p2l has unique direct interactions with jun and its kinase jun kinase (JNK), blocked by the 96-110 and 115-126 peptides. The JNK-jun pathway interacts strongly with the raf-MEK-MAP kinase (MAPK) pathway; dominant negative raf blocks JNK-induced maturation and a newly discovered JNK inhibitor, glutathione-S-transferase (GST), blocks raf-induced maturation. Since the x-ray structures of p21 bound to the ras binding domain of raf (RBD), SOS (guanine nucleotide exchange protein) and GAP (GTPase activating protein), have been determined, we will use molecular modeling studies to determine domains of these proteins that change conformation when bound to oncogenic p21, synthesize peptides corresponding to these domains and test their abilities to block Val 12-p2l selectively. All peptides found to block Val l2-p21 selectively in oocytes will be introduced into mammalian cancer cells either attached to leader sequences or encoded in plasmids to test their abilities to block cell proliferation. Similarly identified GST domains will be tested for their abilities to affect GST-JNK interactions. Since the Val 12-p2 1-induced raf and iNK pathways are closely linked, we will determine which proteins on each pathway cross-activate one another using protein-specific inhibitors that will also be assayed for their abilities to block the binding of Val 12-p21 to both raf and JNK.


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: 2004 ( Subtotal = $253,980 )
2004	2004	UNIVERSITY HOSPITAL OF DOWNSTATE MEDICAL CENTER	450 CLARKSON AVENUE	NEW YORK-KINGS	NY	11203		USA	Cancer Biology Research	000	18	5/5/2004	NON-COMPETING CONTINUATION	$253,980
														Subtotal = $253,980

Issue Date FY: 2003 ( Subtotal = $253,980 )
2003	2003	UNIVERSITY HOSPITAL OF DOWNSTATE MEDICAL CENTER	450 CLARKSON AVENUE	NEW YORK-KINGS	NY	11203		USA	Cancer Biology Research	000	17	5/20/2003	NON-COMPETING CONTINUATION	$253,980
														Subtotal = $253,980

Issue Date FY: 2002 ( Subtotal = $253,980 )
2002	2002	UNIVERSITY HOSPITAL OF DOWNSTATE MEDICAL CENTER	450 CLARKSON AVENUE	NEW YORK-KINGS	NY	11203		USA	Cancer Biology Research	000	16	8/8/2002	NON-COMPETING CONTINUATION	$253,980
														Subtotal = $253,980

Issue Date FY: 2001 ( Subtotal = $252,320 )
2001	2001	UNIVERSITY HOSPITAL OF DOWNSTATE MEDICAL CENTER	450 CLARKSON AVENUE	NEW YORK-KINGS	NY	11203		USA	Cancer Biology Research	000	15	6/25/2001	COMPETING CONTINUATION	$252,320
														Subtotal = $252,320

Issue Date FY: 2000 ( Subtotal = $113,769 )
2000	2000	NARROWS INSTITUTE FOR BIOMEDICAL RESEARCH, INC	800 POLY PLACE BOX 20	BROOKLYN	NY	11209	KINGS	USA	Cancer Biology Research	000	14	6/1/2000	NON-COMPETING CONTINUATION	$113,769
														Subtotal = $113,769

Issue Date FY: 1999 ( Subtotal = $110,456 )
1999	1999	NARROWS INSTITUTE FOR BIOMEDICAL RESEARCH, INC	800 POLY PLACE BOX 20	BROOKLYN	NY	11209	KINGS	USA	Cancer Biology Research	000	13	6/10/1999	NON-COMPETING CONTINUATION	$110,456
														Subtotal = $110,456

Issue Date FY: 1998 ( Subtotal = $109,893 )
1998	1998	NARROWS INSTITUTE FOR BIOMEDICAL RESEARCH, INC	800 POLY PLACE BOX 20	BROOKLYN	NY	11209	KINGS	USA	Cancer Biology Research	000	12	4/6/1998	COMPETING CONTINUATION	$109,893
														Subtotal = $109,893

Grand Total All Awards = $1,348,378

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PROTEIN STRUCTURE AND ONCOGENESIS

Award Number: R01CA042500

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/1988

PERIOD OF PERFORMANCE END DATE: 06/30/2005

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