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ABSTRACT: Bright/ARID3a/Dril1, a member of the ARID family of transcription factors, is expressed in a highly regulated fashion in B lymphocytes, where it enhances immunoglobulin transcription three- to sixfold. Recent publications from our lab indicated that functional, but not kinase-inactive, Bruton's tyrosine kinase (Btk) is critical for Bright activity in an in vitro model system, yet Bright itself is not appreciably tyrosine phosphorylated. These data suggested that a third protein, and Btk substrate, must contribute to Bright-enhanced immunoglobulin transcription. The ubiquitously expressed transcription factor TFII-I was identified as a substrate for Btk several years ago. In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels. These data suggest that Bright functions as a three-component protein complex in the immunoglobulin locus and tie together previous data indicating important roles for Btk and TFII-I in B lymphocytes.
Molecular and Cellular Biology 07/2006; 26(12):4758-68. · 5.53 Impact Factor
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ABSTRACT: Reproduction, or the faithful passage of genetic information from one cell to its progeny, is central to life. To achieve reproduction faithfully cells have developed the cell cycle during which error-free replication of DNA, followed by division of the nucleus and partitioning of the cytoplasm yields two daughter cells. Prior to committing to reproduction, cells must sense mitogen levels in their environment and transduce those signals to the nucleus through a series of biochemical steps, resulting in spatial and/or temporal activation of genes that will drive cell cycle progression past the restriction point and initiate DNA replication. One way external signals are transmitted to the nucleus is via mitogen inducible transcription factors that shuttle between the cytoplasm and nucleus. Here we introduce a newly discovered pathway by which TFII-I, a growth signal induced transcription factor, operates in the prerestriction point and mitogen dependent phase of the cell cycle. We also discuss a potential role for TFII-I in DNA repair and how it might be involved in signal dependent DNA repair versus cell cycle.
Cell cycle (Georgetown, Tex.) 03/2006; 5(4):356-9. · 5.36 Impact Factor
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ABSTRACT: The multifunctional transcription factor TFII-I is tyrosine phosphorylated in response to extracellular growth signals and transcriptionally activates growth-promoting genes. However, whether activation of TFII-I also directly affects the cell cycle profile is unknown. Here we show that under normal growth conditions, TFII-I is recruited to the cyclin D1 promoter and transcriptionally activates this gene. Most strikingly, upon cell cycle arrest resulting from genotoxic stress and p53 activation, TFII-I is ubiquitinated and targeted for proteasomal degradation in a p53- and ATM (ataxia telangiectasia mutated)-dependent manner. Consistent with a direct role of TFII-I in cell cycle regulation and cellular proliferation, stable and ectopic expression of wild-type TFII-I increases cyclin D1 levels, resulting in accelerated entry to and exit from S phase, and overcomes p53-mediated cell cycle arrest, despite radiation. We further show that the transcriptional regulation of cyclin D1 and cell cycle control by TFII-I are dependent on its tyrosine phosphorylation at positions 248 and 611, sites required for its growth signal-mediated transcriptional activity. Taken together, our data define TFII-I as a growth signal-dependent transcriptional activator that is critical for cell cycle control and proliferation and further reveal that genotoxic stress-induced degradation of TFII-I results in cell cycle arrest.
Molecular and Cellular Biology 01/2006; 25(24):10940-52. · 5.53 Impact Factor
