A major strength of the Program is the integration of changes in gene regulation with mouse models of cancer and relating these results to human cancer. The overall goals of the current Program is to investigate the roles of both short and long non-coding RNAs in the development of cancer and the importance of the Rb-E2F pathway in cell death and malignancy. miRNAs probably interact with half of all mRNAs, suppress the level of expression of most of these mRNAs by less than two fold, and yet clearly modulate the development of cancer in mouse models. These small RNAs regulate growth and cell death genes, both modulators of tumor growth, and they also shape developmental transitions. The first Overall Aim of the Program is to Investigate the effects of loss of miRNA functions on cell viability, developmental processes and the development of malignancies. The three projects are investigating the general roles of miRNAs in gene regulation including their mechanisms of action, the consequence of loss of all miRNAs in Dicer null cell lines, and the relationship between miRNAs and differentiation of mesenchymal tumors and stem cells. Targeted mouse genetics will be used to investigate the roles of miRI43-145 cluster in development and tumor suppression. This will involve exploration of the effects of activation of this family of miRNAs in tumors in vivo. The second Overall Aim is to Explore the roles of other types of non-coding RNAs in normal and malignant cells. The population of non-coding RNAs will be characterized in Dicer null and tumor cells in search of RNAi-related transcriptional regulation. This includes further investigation of possible Argonaute functions in the nucleus and the roles of non-coding RNAs generated from most promoters by divergent transcription. The large intervening non-coding RNAs (lincRNAs) regulated by p53. and their roles in tumor biology will be investigated using targeted mouse genetics. The third Overall Aim is to investigate the interactions of tumor suppressor genes Rb and p53 and non-coding RNAs in control of cancer and the plasticity of the differentiation state of cells. The relationship of line RNAs and p53 and of Rb and miRNAs in developmental transition and in maintaining cell state will be investigated. The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied.

Public Health Relevance

The recent recognition of small RNAs in gene regulation has opened new avenues to investigate and possibly diagnose and treat cancer. miRNAs control tumor phenotypes but less is known about the tumor activities of other types of small RNAs and long non-coding RNAs. Tumor suppressor pathways containing Rb and p53 control cell death, migration and differentiation as well as expression of non-coding RNAs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA042063-27
Application #
8471656
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (J1))
Program Officer
Mietz, Judy
Project Start
1997-05-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
27
Fiscal Year
2013
Total Cost
$1,353,765
Indirect Cost
$505,816
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Zamudio, Jesse R; Kelly, Timothy J; Sharp, Phillip A (2014) Argonaute-bound small RNAs from promoter-proximal RNA polymerase II. Cell 156:920-34
Xue, Wen; Dahlman, James E; Tammela, Tuomas et al. (2014) Small RNA combination therapy for lung cancer. Proc Natl Acad Sci U S A 111:E3553-61
Wu, Xuebing; Scott, David A; Kriz, Andrea J et al. (2014) Genome-wide binding of the CRISPR endonuclease Cas9 in mammalian cells. Nat Biotechnol 32:670-6
Xue, Wen; Chen, Sidi; Yin, Hao et al. (2014) CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature 514:380-4
Dimitrova, Nadya; Zamudio, Jesse R; Jong, Robyn M et al. (2014) LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Mol Cell 54:777-90
Yin, Hao; Xue, Wen; Chen, Sidi et al. (2014) Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol 32:551-3
Maynard, M A; Ferretti, R; Hilgendorf, K I et al. (2014) Bmi1 is required for tumorigenesis in a mouse model of intestinal cancer. Oncogene 33:3742-7
Gurtan, Allan M; Ravi, Arvind; Rahl, Peter B et al. (2013) Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts. Genes Dev 27:941-54
Leung, Anthony K L; Sharp, Phillip A (2013) Quantifying Argonaute proteins in and out of GW/P-bodies: implications in microRNA activities. Adv Exp Med Biol 768:165-82
Wu, Xuebing; Sharp, Phillip A (2013) Divergent transcription: a driving force for new gene origination? Cell 155:990-6

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