APE EXPRESSION/LEUKEMIA RESPONSE TO CHEMO/RADIOTHERAPY

Project: Research project

Description

DESCRIPTION: DNA damage in the form of apurinic/apyrimidinic (AP) sites is induced by cytotoxic agents resulting in base substitution mutations and blocks to DNA replication. The DNA base excision repair (BER) enzyme, AP endonuclease (APE), is a multifunctional protein involved in DNA base excision repair, oxidative signaling, transcription factor regulation, cell cycle control, and apoptosis. APE is essential for the repair of AP sites thus maintaining cellular and genetic integrity. Deficient expression of APE results in a heightened sensitivity to radiation and alkylating agents with resultant tissue damage. Logically it follows that APE may also play a role in the sensitivity to malignant cells to DNA damaging therapeutic agents. Many cancer therapeutic agents will induce apoptosis or programmed cell death, however little is known about the relationship of DNA repair enzymes (particularly BER) and apoptosis. Preliminary observations indicating that APE expression can be suppressed in myeloid leukemia cells by retinoic acid or DMSO while inducing apoptosis, has led to the hypothesis that: Decreased expression of APE is functionally related to apoptosis in myeloid leukemia cells. The specific aims are: Specific Aim #1 What is the relationship of APE expression to myeloid leukemia cell differentiation and apoptosis? Specific Aim 2: What is the role of APE protein phosphorylation in APE expression, function and apoptosis. Specific Aim #3: Determination of the molecular mechanisms that are responsible for down-regulation of APE expression upon induction of apoptosis. We propose to initiate studies on the relationship of APE expression and phosphorylation to cell differentiation, apoptosis, and sensitivity to cytotoxic agents, with the long-term goal of developing ways to enhance the chemo/radio sensitivity of leukemia cells by manipulating expression of APE.
StatusFinished
Effective start/end date8/1/985/31/03

Funding

  • National Institutes of Health: $258,571.00
  • National Institutes of Health
  • National Institutes of Health: $266,257.00
  • National Institutes of Health: $257,064.00

Fingerprint

DNA-(Apurinic or Apyrimidinic Site) Lyase
Leukemia
Radiotherapy
Apoptosis
Myeloid Leukemia
Myeloid Cells
DNA Repair
Cytotoxins
Cell Differentiation
DNA
Phosphorylation
DNA Repair Enzymes
Endonucleases
Alkylating Agents
Radiation Tolerance
Dimethyl Sulfoxide
Cell Cycle Checkpoints
Tretinoin
DNA Replication
Radio

ASJC

  • Medicine(all)