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.
|Effective start/end date||8/1/98 → 5/31/03|
- 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