The most common target for chromosomal translocation in childhood leukemia is the E2A gene, which encodes the basic-helix-loop-helix transcription factors E12 and E47. These nearly ubiquitously expressed proteins have a demonstrated growth suppressive role in mammalian cells. It appears that downregulation of E2A activity is necessary for normal cell cycle progression, involving a combination of transcriptional control of the E2A gene, degradation of E2A proteins, and direct inhibition by Id proteins. Using the yeast two hybrid system, this laboratory has cloned mUBC9, a cDNA encoding a novel murine ubiquitin conjugating enzyme that may participate in the degradation of E2A proteins. This research proposal investigates the degradation of E2A protein in mammalian cells, and evaluates the role of the ubiquitin-proteasome pathway in this process, particularly the role of the mUBC9 enzyme. Data from other laboratories suggests that the yeast homolog of mUBC9 is critical to normal cell cycle progression, supporting a possible functional link between mUBC9 and growth regulatory transcription factors such as E2A proteins. The following specific aims are proposed: 1) Determine the degradation pathway of mammalian E2A proteins; 2) Evaluate the role of mUBC9 in E2A degradatio; 3) Define determinants of E2A degradation; and 4) Evaluate proposed regulatory mechanisms for E2A degradation. Accomplishment of these specific aims will provide a more general framework for understanding mechanism of regulated degradation of transcription factors as a means of controlling mammalian cell growth and differentiation. This has implications for the investigation of novel mechanisms of growth regulation with a newly demonstrated potential in oncogenesis.
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