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THE ROLE OF RR IN CHEMOTHERAPEUTIC DRUG RESISTANCE

Award Number: R01CA072767
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/1997
PERIOD OF PERFORMANCE END DATE: 06/30/2006

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THE ROLE OF RR IN CHEMOTHERAPEUTIC DRUG RESISTANCE - DESCRIPTION (provided by applicant): Ribonucleotide reductase (RR) is an important therapeutic target. Therefore, understanding the function and regulation of the RR gene, and development of new RR inhibitors may have a direct impact on cancer treatment. Our long-term goal is to better understand the molecular mechanism of RR gene regulation, and the role of RR in chemotherapeutic drug resistance. We have shown that gemcitabine resistant as well as hydroxyurea resistant clones both overexpress the RR small subunit, hRRM2, mRNA and RR protein. Further studies confirmed that these drug-resistant tumor cell clones are associated with nucleus factor Y (NFY) binding to the RR promoter. Therefore, in Specific Aim I we will investigate whether hRRM2 overexpression in drug resistant cells is directed through transcription factor regulation o: the hRRM2 promoter. Promoter binding of NPY and a new transcription factor, band c, will be examined by gel-shift analysis and specificity will be confirmed by affinity chromatography. The functional consequences of NFY and band c in the regulation of hRRM2 expression will be examined in transfection assays. Since p53R2 is an integral part of the RR gene family, we are also intrigued by the possibility that interactions between different subunits of RR are important. In Specific Aim II, we will examine the interactions of p53R2, hRRM2, and hRRM1 (the RR large subunit), identify interacting domains, and examine the biochemical characteristics of such subunit interactions. A mammalian expression system will be employed to examine in vitro recombination of each subunit. Deletion analysis and mutagenesis will be performed to examine interacting domains and results will be confirmed by affinity chromatography. The plasmid vector containing p53R2 will be transfected into cloned drug-resistant cells for study in vivo. Once we clarify the interaction among RR subunits, we will explore the role of p53 in RR regulation. Our immunoprecipitation results have shown that both p53R2 and hRRM2 can bind to wild-type p53. Our hypothesis is that RR subunit composition may be regulated by p53. In specific aim ifi, we will confirm the protein interaction between p53R2 and wild-type p53 using a yeast two hybrid system. These findings will be confirmed by immunoprecipitation and Western blotting. The effect o wild-type p53 on RR activity and subunit composition will also be examined by transfecting wild-type p53 into cell lines expressing mutant p53. These experiments will help to confirm the interactions between p53R2, hRRM2, and p53. Finally, in Specific Aim IV, we will investigate the molecular pharmacology of a new RR inhibitor, HSC 1 that inhibits human cancer cells through an interaction with hRRM2. Taken together, our proposed studies will provide an integrated evaluation of the molecular control of RR-mediated chemotherapeutic drug resistance.


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: 2005 ( Subtotal = $249,375 )
2005	2005	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	9	5/24/2005	NON-COMPETING CONTINUATION	$249,375
														Subtotal = $249,375

Issue Date FY: 2004 ( Subtotal = $259,375 )
2004	2004	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	8	6/24/2004	NON-COMPETING CONTINUATION	$259,375
														Subtotal = $259,375

Issue Date FY: 2003 ( Subtotal = $249,375 )
2003	2003	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	7	9/18/2003	OTHER REVISION	$249,375
														Subtotal = $249,375

Issue Date FY: 2002 ( Subtotal = $249,375 )
2002	2002	CITY OF HOPE NATIONAL MEDICAL CENTER	1500 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	6	7/15/2002	COMPETING CONTINUATION	$249,375
														Subtotal = $249,375

Grand Total All Awards = $1,007,500

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THE ROLE OF RR IN CHEMOTHERAPEUTIC DRUG RESISTANCE

Award Number: R01CA072767

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/1997

PERIOD OF PERFORMANCE END DATE: 06/30/2006

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