Retinoblastoma is a malignant pediatric tumor in which mutations in the RB gene occur in the vast majority of cases. While retinoblastoma is initiated by RB inactivation, the steps between RB loss and tumorigenesis are not well understood. This proposal aims to investigate the changes that occur as retinoblastomas initiate and progress to malignancy. Mechanisms of cooperation with RB deletion in retinoblastoma may be broadly relevant for many human cancers. I hypothesize that secondary alterations help the retinoblastoma cell of origin evade a pathway to cell cycle exit controlled by the Rb family member, p130. These secondary alterations may alter the activity of p130 through control of cyclin dependent kinases (CDKs) or may act at other points in the pathway (e.g. by regulating E2F transcription factors). Moreover, I hypothesize that evasion of p130-controlled cell cycle exit in RB-deficient cells may be important not only for retinoblastoma, but for other tumor types. To test these hypotheses, we will use a combination of mouse genetics, cell culture studies and investigation of primary human and murine tumor samples. These studies will use the power of mouse models to determine definitively whether candidate Rb-cooperating genes are important for tumorigenesis and to understand how these co-operating genes synergize with Rb loss.
Specific Aim 1 : Investigate the mechanism by which Arf functions as tumor suppressor gene in retinoblastoma.
Specific Aim 2 : Assess whether N-myc alters the activity of the pRB family members in promoting tumorigenesis. This work has important implications for understanding many human tumor types that exhibit RB pathway inactivation. If pathways controlled by RB family members are functionally inactivated through secondary alterations, then reactivation of such pathways may provide new opportunities for therapeutic intervention.

Public Health Relevance

The RB gene is deleted in many human tumors and the RB pathway is disrupted in virtually every human cancer. Certain cells in the developing retina are exquisitely sensitive to retinoblastoma upon RB gene mutation making retinoblastoma an ideal system to understand mechanisms behind cooperation with RB loss in tumorigenesis. We use mouse models and studies of human retinoblastoma samples to learn how RB- cooperating genes contribute to cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148867-03
Application #
8204720
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Hildesheim, Jeffrey
Project Start
2010-08-12
Project End
2012-07-14
Budget Start
2012-01-01
Budget End
2012-07-14
Support Year
3
Fiscal Year
2012
Total Cost
$205,248
Indirect Cost
$73,678
Name
Carnegie Institution of Washington, D.C.
Department
Type
DUNS #
072641707
City
Washington
State
DC
Country
United States
Zip Code
20005
Cui, Min; Augert, Arnaud; Rongione, Michael et al. (2014) PTEN is a potent suppressor of small cell lung cancer. Mol Cancer Res 12:654-9
Conkrite, Karina; Sundby, Maggie; Mu, David et al. (2012) Cooperation between Rb and Arf in suppressing mouse retinoblastoma. J Clin Invest 122:1726-33
Conkrite, Karina; Sundby, Maggie; Mukai, Shizuo et al. (2011) miR-17~92 cooperates with RB pathway mutations to promote retinoblastoma. Genes Dev 25:1734-45