The goals of the proposed research are to advance our knowledge about how oncogenic transformation perturbs cell differentiation programs and to understand how these perturbations can be reversed to reestablish differentiation and terminal cell divisions in tumor cells. It is now clear that tumor cells can, under appropriate conditions, reinitiate and complete their normal differentiation program. Our approach is to investigate the molecular basis for the block to differentiation present in murine erythroleukemia (MEL) cell lines and the events occurring when the cells are induced to reenter their terminal differentiation program. Recent work in our laboratory indicates that deregulated expression of an Ets family transcription factor, PU.1 (Spi-1), is principally responsible for the block to differentiation present in MEL cells. We purpose to determine the molecular mechanisms by which PU.1 blocks erythroid differentiation. One approach will be to investigate which transcription factor functions of PU.1 are required for blocking MEL cell differentiation and to identify the downstream gene targets that are regulated by PU.1. A parallel approach will be to investigate the possibility that PU.1 blocks differentiation by directly interacting with proteins that are required for red blood cell differentiation. Other studies in our laboratory indicate that changes in expression of cyclin-dependent kinases and their inhibitors may be involved both in the decision of the cells to differentiate and in implementing the final cell divisions. We propose to carry out transfection experiments to determine whether changes in these cell cycle regulators contribute to controlling these two aspects of the differentiation program. Understanding the events occurring in tumor cells when they are forced back into terminal differentiation will contribute to our knowledge about the control of cell proliferation and differentiation as well as provide opportunities for development of therapies based on the capacity of tumor cells to resume terminal cell divisions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA016368-27
Application #
6172409
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
1977-05-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
27
Fiscal Year
2000
Total Cost
$528,766
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Burda, Pavel; Curik, Nikola; Kokavec, Juraj et al. (2009) PU.1 activation relieves GATA-1-mediated repression of Cebpa and Cbfb during leukemia differentiation. Mol Cancer Res 7:1693-703
Stopka, Tomas; Skoultchi, Arthur I (2003) The ISWI ATPase Snf2h is required for early mouse development. Proc Natl Acad Sci U S A 100:14097-102
Starck, J; Doubeikovski, A; Sarrazin, S et al. (1999) Spi-1/PU.1 is a positive regulator of the Fli-1 gene involved in inhibition of erythroid differentiation in friend erythroleukemic cell lines. Mol Cell Biol 19:121-35
Wang, Z F; Sirotkin, A M; Buchold, G M et al. (1997) The mouse histone H1 genes: gene organization and differential regulation. J Mol Biol 271:124-38
Dong, Y; Liu, D; Skoultchi, A I (1995) An upstream control region required for inducible transcription of the mouse H1(zero) histone gene during terminal differentiation. Mol Cell Biol 15:1889-900
Sirotkin, A M; Edelmann, W; Cheng, G et al. (1995) Mice develop normally without the H1(0) linker histone. Proc Natl Acad Sci U S A 92:6434-8
Dong, Y; Sirotkin, A M; Yang, Y S et al. (1994) Isolation and characterization of two replication-dependent mouse H1 histone genes. Nucleic Acids Res 22:1421-8
Das Gupta, R; Morrow, B; Marondel, I et al. (1993) An integrated approach for identifying and mapping human genes. Proc Natl Acad Sci U S A 90:4364-8
Krimer, D B; Cheng, G; Skoultchi, A I (1993) Induction of H3.3 replacement histone mRNAs during the precommitment period of murine erythroleukemia cell differentiation. Nucleic Acids Res 21:2873-9
Dong, Y; Skoultchi, A I; Pollard, J W (1993) Efficient DNA transfection of quiescent mammalian cells using poly-L-ornithine. Nucleic Acids Res 21:771-2

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