Regulation of transcription is a biochemical process affected by the activities of many oncogenes and probably also anti-oncogenes. Alterations in the activities of transcription factors control cell division and differentiation which change during transformation of cells. During the past four years, analysis of the factors essential for initiation of transcription by RNA polymerase II and the structure of sequence-specific factors which regulate this reaction has advanced significantly. The three broad objectives of the grant build on this progress. These objectives are: (1) biochemical definition of the factors and process essential for accurate initiation of transcription by RNA polymerase II, (2) biochemical analysis of the auxiliary factors and mechanism by which sequence-specific DNA binding factors stimulate the rate of initiation by RNA polymerase II, and (3) analysis of the role and mechanism by which transcription factors such as Oct-2, the Helix-loop-helix protein TFEB, and oncogene protein myc regulate growth and development of B cells. Four basal factors are important for the initiation reaction; TFIIA, TFIIB, TFIID, and TFIIe/f. The nature of protein-protein and protein-DNA interactions responsible for directing polymerase II to initiate will be investigated. The Oct-2 protein stimulates expression of the immunoglobulin heavy chain promoter in B cells. The highly related Oct-1 protein, both contain a POU-box domain, does not stimulate the immunoglobulin promoter even though it is equally capable of binding the critical octamer site. The specificity of these two activities in B cells will be studied as well as the role of the conserved POU-box domain. The myc family of proteins has a common structure with the helix-loop-helix protein TFEB. The significance of this structure similarity in regulation of B cell development will be explored.

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Massachusetts Institute of Technology
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