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DISSECTION OF THE FEEDBACK INHIBITION OF C-MYC BY L11

Award Number: K99CA127134
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/08/2009
PERIOD OF PERFORMANCE END DATE: 08/31/2009

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DISSECTION OF THE FEEDBACK INHIBITION OF C-MYC BY L11 - DESCRIPTION (provided by applicant): The c-Myc oncoprotein is a cellular target of great interest because its proper physiological level is essential for normal cell growth and proliferation, while its deregulated overexpression is closely related to many human cancers. Thus c-Myc level and activity must be tightly controlled in cells. In an attempt to understand the regulation of c-Myc, I have recently identified that ribosomal protein L11, a component of the large subunit of the ribosome, inhibits c-Myc transactivation activity and induction of cell proliferation. As L11 is transcriptionally induced by c-Myc, these results lead to an important hypothesis that L11 may act as a critical auto-regulatory feedback inhibitor of c-Myc. My current research focuses on understanding this L11-c-Myc feedback inhibition by further characterizing L11-c-Myc protein-protein interaction, L11 protein-c-myc mRNA interaction, and the inhibitory effect of L11 on c-Myc-enhanced ribosomal biogenesis. My broad, long-term objectives of this application in the independent phase are to study how L11 inhibits c-Myc function and whether L11 suppresses c-Myc's transformation activity in cells and oncogenic activity in vivo. Three specific aims are proposed: 1) To investigate the mechanisms underlying the inhibitory role of L11 on c-Myc activity, I will analyze whether L11 conceals c-Myc transactivation domain on its target gene promoters; 2) To investigate whether L11 regulates c-myc mRNA level and translation through microRNA-guided pathways, I will investigate whether L11 binds to 3'-UTR of c-myc mRNA with RNA interference silencing complex (RISC) to degrade c-myc mRNA and/or silence its translation; 3) To investigate the physiological significance of the inhibitory effect of L11 on c-Myc, I will determine whether L11-c-Myc loop plays a role in normal cellular growth response and also in response to certain types of cellular stress, and whether L11 suppresses c-Myc-induced transformation in cells and tumor formation in mice. Achieving these aims from this project using biochemical, cellular and molecular biological, and genetic approaches would demonstrate a novel tumor suppressive function of L11 by inhibiting c-Myc. Since ablating c-Myc expression leads to regression of c-Myc-induced tumors in multiple tissues, results from the mechanistic studies on L11's inhibitory effect on c-Myc would offer useful information for developing antitumor drugs that target c-Myc in cancer patients.


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: 2009 ( Subtotal = $0 )
2009	2008	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Cancer Research Manpower	000	2	4/9/2009	NON-COMPETING CONTINUATION	-$54,543
2009	2008	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Research Manpower	001	3	4/9/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$54,543
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $94,188 )
2008	2008	INDIANA UNIVERSITY, BLOOMINGTON	BRYAN 215C	BLOOMINGTON	IN	47405	MONROE	USA	Cancer Research Manpower	000	2	8/29/2008	NON-COMPETING CONTINUATION	$94,188
														Subtotal = $94,188

Issue Date FY: 2007 ( Subtotal = $91,800 )
2007	2007	INDIANA UNIVERSITY, BLOOMINGTON	BRYAN 215C	BLOOMINGTON	IN	47405	MONROE	USA	Cancer Research Manpower	000	1	8/31/2007	NEW	$91,800
														Subtotal = $91,800

Grand Total All Awards = $185,988

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DISSECTION OF THE FEEDBACK INHIBITION OF C-MYC BY L11

Award Number: K99CA127134

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/08/2009

PERIOD OF PERFORMANCE END DATE: 08/31/2009

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