REGULATORS OF THE MAMMALIAN REPLICATION GENES

University Of Illinois At Chicago, Chicago IL

Investigators

Linked publications & trials

Abstract

Cancer cells, unlike normal cells, over-express the genes that are involved in replication. The transcription factors of the E2F family (E2Fs) are centrally important in this regard because they regulate expression of several key genes that are essential for replication and cell cycle progression. Also, E2Fs are targets of oncogenes, tumor suppressor genes and cell cycle regulators. Cellular pathways that control E2Fs are frequently mutated in human cancers, suggesting that they play critical roles in preventing oncogenesis. The goal of this proposal is to elucidate the mechanisms by which E2Fs control expression of the replication genes, which will be extremely valuable in designing therapeutic interventions. The proposal is based on the observation that DDB (which was identified as an activity that binds UV-damaged DNA) functions as a transcription partner of the E2F-family factor E2F1. DDB binds to the activation domain of E2F1 and stimulates E2F1-activated transcription. Moreover, expression of DDB overcomes the transcriptional inhibitory function of the Rb tumor suppressor. We propose to investigate the hypothesis that DDB is important for the regulated expression of the replication genes t the G1/S-phase boundary. Furthermore, the mechanism by which DDB stimulates transcription and overcomes Rb-inhibition will be investigated. The specific aims are: 1. Is DDB essential for the E2F1-activated expression of the replication genes? 2. Is DDB a target of the cell cycle regulators such as p16Ink4a, p27Kip1 and p21Cip1? Does DDB compete with the tumor suppressor Rb for E2F1? 3. What is the mechanism by which DDB cooperates with E2F1 to stimulate transcription? 4. Is E2F1-DDB interaction regulated by damaged-DNA?