CONTROL OF DIFFERENTIATION OF ERYTHROLEUKEMIC CELLS

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date12/31/894/30/04

Funding

  • National Cancer Institute: $536,417.00
  • National Cancer Institute
  • National Cancer Institute: $558,710.00
  • National Cancer Institute: $75,000.00
  • National Cancer Institute
  • National Cancer Institute: $528,766.00

ASJC

  • Genetics
  • Molecular Biology

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