Abstract

This proposal consisting of five projects focuses on the analysis of the mechanisms leading to malignant transformation of hematopoietic cells with emphasis on retroviruses and oncogenes. The theme is to define the genes that contribute to malignant transformation resulting in leukemias and lymphomas and the mechanisms by which oncogenes and viruses interfere with normal differentiation pathways of various hematopoietic lineages. We will focus on five oncogenes, myb, fos, jun, abl and ras to increase our understanding of their mode of action at the molecular and cellular level. We will explore the possibility of using the MoMuLV as a tool to identify potential oncogene candidates, by insertional mutagenesis in vitro, on a growth-factor dependent cell line. We will study the molecular mechanism of action of newly identified transforming gene of a recently described virus (HHV6) to understand its mechanism of action and role in human hematopoietic malignancies. Finally, we will look at the role played by HIV1 and DNA viruses to define the molecular basis of hyperplasia in AIDS patients and to determine the criteria for identifying progressive lymphomas at an early stage of development.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA052009-02
Application #
3094486
Study Section
Special Emphasis Panel (SRC (U1))
Project Start
1991-02-01
Project End
1996-01-31
Budget Start
1992-08-15
Budget End
1993-01-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Temple University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122

  Publications

Schultz, D C; Friedman, J R; Rauscher 3rd, F J (2001) Targeting histone deacetylase complexes via KRAB-zinc finger proteins: the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the Mi-2alpha subunit of NuRD. Genes Dev 15:428-43
Capili, A D; Schultz, D C; RauscherIII, F J et al. (2001) Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains. EMBO J 20:165-77
Fredericks, W J; Ayyanathan, K; Rauscher 3rd, F J (2001) Regulating the neoplastic phenotype using engineered transcriptional repressors. Cancer Lett 162 Suppl:S23-S32
Peng, H; Begg, G E; Schultz, D C et al. (2000) Reconstitution of the KRAB-KAP-1 repressor complex: a model system for defining the molecular anatomy of RING-B box-coiled-coil domain-mediated protein-protein interactions. J Mol Biol 295:1139-62
Fredericks, W J; Ayyanathan, K; Herlyn, M et al. (2000) An engineered PAX3-KRAB transcriptional repressor inhibits the malignant phenotype of alveolar rhabdomyosarcoma cells harboring the endogenous PAX3-FKHR oncogene. Mol Cell Biol 20:5019-31
Ayyanathan, K; Fredericks, W J; Berking, C et al. (2000) Hormone-dependent tumor regression in vivo by an inducible transcriptional repressor directed at the PAX3-FKHR oncogene. Cancer Res 60:5803-14
Li, X; Peng, H; Schultz, D C et al. (1999) Structure-function studies of the BTB/POZ transcriptional repression domain from the promyelocytic leukemia zinc finger oncoprotein. Cancer Res 59:5275-82
Reeves, F C; Burdge, G C; Fredericks, W J et al. (1999) Induction of antisense Pax-3 expression leads to the rapid morphological differentiation of neuronal cells and an altered response to the mitogenic growth factor bFGF. J Cell Sci 112 ( Pt 2):253-61
Ryan, R F; Schultz, D C; Ayyanathan, K et al. (1999) KAP-1 corepressor protein interacts and colocalizes with heterochromatic and euchromatic HP1 proteins: a potential role for Kruppel-associated box-zinc finger proteins in heterochromatin-mediated gene silencing. Mol Cell Biol 19:4366-78
Rauscher 3rd, F J; Morris, J F; Fredericks, W J et al. (1998) Characterization of monoclonal antibodies directed to the amino-terminus of the WT1, Wilms' tumor suppressor protein. Hybridoma 17:191-8

Showing the most recent 10 out of 59 publications