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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA042063-09
Application #
3750821
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Gao, Ang; Shrinivas, Krishna; Lepeudry, Paul et al. (2018) Evolution of weak cooperative interactions for biological specificity. Proc Natl Acad Sci U S A 115:E11053-E11060
Dubbury, Sara J; Boutz, Paul L; Sharp, Phillip A (2018) CDK12 regulates DNA repair genes by suppressing intronic polyadenylation. Nature 564:141-145
Parisi, Tiziana; Balsamo, Michele; Gertler, Frank et al. (2018) The Rb tumor suppressor regulates epithelial cell migration and polarity. Mol Carcinog 57:1640-1650
Sabari, Benjamin R; Dall'Agnese, Alessandra; Boija, Ann et al. (2018) Coactivator condensation at super-enhancers links phase separation and gene control. Science 361:
Chiu, Anthony C; Suzuki, Hiroshi I; Wu, Xuebing et al. (2018) Transcriptional Pause Sites Delineate Stable Nucleosome-Associated Premature Polyadenylation Suppressed by U1 snRNP. Mol Cell 69:648-663.e7
JnBaptiste, Courtney K; Gurtan, Allan M; Thai, Kevin K et al. (2017) Corrigendum: Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1-3 family. Genes Dev 31:1066
Hnisz, Denes; Shrinivas, Krishna; Young, Richard A et al. (2017) A Phase Separation Model for Transcriptional Control. Cell 169:13-23
JnBaptiste, Courtney K; Gurtan, Allan M; Thai, Kevin K et al. (2017) Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1-3 family. Genes Dev 31:674-687
Suzuki, Hiroshi I; Young, Richard A; Sharp, Phillip A (2017) Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis. Cell 168:1000-1014.e15
Mori, Munemasa; Hazan, Renin; Danielian, Paul S et al. (2017) Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis. Nat Commun 8:15857

Showing the most recent 10 out of 218 publications