TFII-I is a ubiquitously expressed, signal induced transcription factor. TFII-I contains a number of unique structural properties that include a leucine zipper, nuclear localization signal and six helix-loop-helix repeats that are conserved across species and family members. In humans, a hemizygous deletion within chromosome 7q11.23, a region that encodes for TFII-I and its structurally related family member, BEN, is associated with a neurodevelopmental disorder known as William-Beurens syndrome (WBS).
While TFII-I’s role in growth factor induced proliferation is well characterized, TFII-I was recently identified as a phosphorylated constituent in a TGF-β1 phosphoproteomic screen, suggesting that it performs additional hitherto unidentified functions in a signal dependent manner. To determine if TFII-I contributes to growth arrest, we made use of the WEHI-231 B lymphoma cell line which undergoes growth arrest in response to both TGF-β1 and antigenic signaling. Due to intrinsic pathway specific mutations, WEHI-231 cells are characterized by increased nuclear levels of NFκB thereby exhibiting similar transformation characteristics as a subset of ABC derived Diffuse Large B cell Lymphomas. TFII-I knockdown results in a growth arrest defect characterized by elevated c-myc expression, decreased expression of the cell cycle inhibitory proteins p21 and p27, and defects in NFκB regulation. Therefore, TFII-I performs a crucial function in controlling NFκB specific pathways in response to cytostatic signals and further suggests that a TFII-I-NFκB regulatory network intersect during proliferation.
Furthermore, given our interest in understanding how TFII-I contributes to cellular proliferation, we sought to identify additional functions and transcriptional targets during the S-G2/M phase of the cell cycle. Posttranscriptional silencing of TFII-I results in delayed cell cycle progression throughout the S phase whereas TFII-I is dispensable for successful entry and execution of mitosis. Whole genome microarray profiling indicates that TFII-I does not transcriptionally regulate the expression of G2/M specific genes suggesting that TFII-I performs a nontranscriptional role to promote S phase progression.
|Advisor:||Roy, Ananda L., Bunnell, Stephen|
|Commitee:||Brodeur, Peter, Bunnell, Stephen, Poltorak, Alexander|
|School:||Sackler School of Graduate Biomedical Sciences (Tufts University)|
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 70/03, Dissertation Abstracts International|
|Keywords:||Cell cycle, NF-kappaB, Posttranscriptional silencing, TFII-I|
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