Title |
Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
|
Institution |
MASSACHUSETTS INSTITUTE OF TECHNOLOGY, CAMBRIDGE, MA
|
Principal Investigator |
Sharp, Phillip
|
NCI Program Director |
Judy Mietz
|
Cancer Activity |
DNA Chromosome Aberrations
|
Division |
DCB
|
Funded Amount |
$1,430,618
|
Project Dates |
05/01/1997 - 08/31/2011
|
Fiscal Year |
2009
|
Project Type |
Grant
|
Research Topics w/ Percent Relevance |
Cancer Types w/ Percent Relevance |
Cancer (100.0%)
Childhood Cancers (50.0%)
Interferon (5.0%)
Metastasis (25.0%)
|
Lung (25.0%)
Melanoma (25.0%)
|
Research Type |
Resources and Infrastructure
Endogenous Factors in the Origin and Cause of Cancer
|
Abstract |
Cancer is a major disease burden and one hope of changing this is to develop new treatments through a
better understanding of the disease. Recent discoveries concerning the activities of short RNAs in mammals
may provide both new insights and new treatments of cancer. A common goal of this Program is to
investigate the roles of short RNAs, such as microRNAs, in regulation of genes in normal and cancer cells.
There is strong and rapidly growing evidence suggesting that changes in miRNA regulation are related to
malignant transformation and in fact could be a critical event in oncogenic transformation. The function of
the mir-17-92-1 cluster which is frequently overexpressed/amplified in a subset of human cancers will be
investigated by creation of specific mutations of these microRNAs in the context of mouse models of cancer.
Changes in microRNA populations in normal cells and tumor cells of the same developmental state will be
analyzed using both bead-array technology as well as new cloning technology. Vectors with regulated
expression of a short hairpin RNA which generates a specific siRNA for silencing a gene will be developed
for transgenic analysis of pathways. Additionally, methods will be tested for screening of small libraries of
shRNA-lentiviral vectors to identify genes which, when silenced, either inhibit or stimulate tumor
development. Furthermore, libraries of retro viral vectors expressing shRNAs will be used in screens to
identify (a) genes that modulate the proliferation and/or survival of pRB-deficient cells , (b) genes that
modulate the rate of development of a K-ras-driven lung cancer model, and (c) genes important for the
differentiation of ES cells. The potential role of short RNAs in transcriptional silencing will be investigated in
embryonic stem cells. These processes could be important for epigenetic silencing and genomic stability of
cancer cells. ES cells will also be studied for the role of miRNAs in development and proliferation. Changes
in the spectrum of microRNAs and siRNAs during T-cell development will be characterized using a cloning
technology which requires small amounts of RNAi. Activation of the Arf promoter is an early signal in
oncogenic transformation. This promoter is silenced under normal conditions by the E2F3B protein, linking
the p19Arf-mdm2-p53 pathway to the p16INK4a-cycD/cdk4-pRB-EdF pathway. The role of E2F3B complexes
and other E2F factors in regulation of the Arf promoter will be studied. |