Opposing functions of TFII-I spliced isoforms in growth factor-induced gene expression.
Multifunctional transcription factor TFII-I has two spliced isoforms (Delta and beta) in murine fibroblasts. Here we show that these isoforms have distinct subcellular localization and mutually exclusive transcription functions in the context of growth factor signaling. In the absence of signaling, TFII-Ibeta is nuclear and recruited to the c-fos promoter in vivo. But upon growth factor stimulation, the promoter recruitment is abolished and it is exported out of the nucleus. Moreover, isoform-specific silencing of TFII-Ibeta results in transcriptional activation of the c-fos gene. In contrast, TFII-IDelta is largely cytoplasmic in the resting state but translocates to the nucleus upon growth factor signaling, undergoes signal-induced recruitment to the same site on the c-fos promoter, and activates the gene. Importantly, activated TFII-IDelta interacts with Erk1/2 (MAPK) kinase in the cell cytoplasm and imports the Erk1/2 to the nucleus, thereby transducing growth factor signaling. Our results identify a unique growth factor signaling pathway controlled by opposing activities of two TFII-I spliced isoforms.
Hakre
Shweta
S
Program in Immunology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, Massachusetts 02111, USA.
Tussie-Luna
María Isabel
MI
Ashworth
Todd
T
Novina
Carl D
CD
Settleman
Jeffrey
J
Sharp
Phillip A
PA
Roy
Ananda L
AL
D016475:3T3 Cells; D017398:Alternative Splicing; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction; D019473:Transcription Factors, TFII / Q000737:chemistry*
C486330:Gtf2i protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D016760:Proto-Oncogene Proteins c-fos; D019473:Transcription Factors, TFII