Abstract

Revised Abstract: Rhabdomyosarcoma (RMS) is the third most common soft tissue sarcoma in children. Alveolar RMS is characterized by the t(2;13) that results in the expression of the activated transcription factor Pax3-FKHR. The long-term goal of this project is to identify the tumorigenic events that result in alveolar RMS. Because Pax3 plays an important role in the embryonic development of muscles, the proposed hypothesis is that disruption of Pax3-regulated gene expression by Pax3-FKHR is crucial for the development of alveolar RMS. However, expression of Pax3- FKHR in mice is insufficient to recapitulate disease. Forced expression of Pax3 and Pax3-FKHR in primary mouse myoblasts increases their rate of proliferation, and Pax3-FKHR, but not Pax3, blocks their differentiation. Therefore, the following specific aims are proposed:
Aim 1) The mechanism by which Pax3-FKHR causes the acceleration of the cell cycle in primary myoblasts and the transcriptional targets of Pax3 and Pax3-FKHR in myoblasts will be identified.
This aim will be accomplished by analyzing the interactions between Pax3-FKHR and cell-cycle regulators and by performing cDNA microarray analyses of myoblasts.
Aim 2) The genes that cooperate with Pax3-FKHR in transforming primary myogenic in vitro and in vivo will be identified. Complementary mutagenesis approaches will be used to identify the additional genetic changes that are essential for tumorigenic transformation. Such changes will be introduced into mouse models to test their ability to cooperate with Pax3-FKHR in tumorigenesis. The relevance of such changes in human alveolar RMS will be determined by testing for disease-specific changes in expression of these genes in human RMS cell lines and tumors. Together, these studies will provide valuable insights into the disruption of molecular pathways that cause alveolar RMS in children. This understanding may ultimately result in the identification of new targets that will lead to improved therapies for this disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA071907-06
Application #
6492307
Study Section
Project Start
1996-08-01
Project End
2006-05-31
Budget Start
Budget End
Support Year
6
Fiscal Year
2001
Total Cost
$241,412
Indirect Cost

  Institution

Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105

  Publications

Dumitrache, Lavinia C; McKinnon, Peter J (2017) Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease. Mech Ageing Dev 161:121-129
Ribeiro, Raul C; Antillon, Federico; Pedrosa, Francisco et al. (2016) Global Pediatric Oncology: Lessons From Partnerships Between High-Income Countries and Low- to Mid-Income Countries. J Clin Oncol 34:53-61
Doherty, Joanne R; Nilsson, Lisa M; Kuliyev, Emin et al. (2014) Embryonic Expression and Function of the Xenopus Ink4d Cyclin D-Dependent Kinase Inhibitor. Cell Dev Biol 3:
Morfouace, Marie; Shelat, Anang; Jacus, Megan et al. (2014) Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma. Cancer Cell 25:516-29
Wang, Yuefeng; Fisher, John C; Mathew, Rose et al. (2011) Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21. Nat Chem Biol 7:214-21
Trikha, Prashant; Sharma, Nidhi; Opavsky, Rene et al. (2011) E2f1-3 are critical for myeloid development. J Biol Chem 286:4783-95
Doghman, Mabrouka; El Wakil, Abeer; Cardinaud, Bruno et al. (2010) Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res 70:4666-75
Pottier, N; Paugh, S W; Ding, C et al. (2010) Promoter polymorphisms in the ?-2 adrenergic receptor are associated with drug-induced gene expression changes and response in acute lymphoblastic leukemia. Clin Pharmacol Ther 88:854-61
Huang, Danny T; Ayrault, Olivier; Hunt, Harold W et al. (2009) E2-RING expansion of the NEDD8 cascade confers specificity to cullin modification. Mol Cell 33:483-95
Forget, Antoine; Ayrault, Olivier; den Besten, Willem et al. (2008) Differential post-transcriptional regulation of two Ink4 proteins, p18 Ink4c and p19 Ink4d. Cell Cycle 7:3737-46

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