Differential splicing generates Tvl-1/RFXANK isoforms with different functions.
Earlier studies have shown that Tvl-1 gives rise to at least two differentially spliced mRNAs, one of which (Tvl-S) encodes a protein that lacks amino acids 91-112. DNA binding of RFX complexes assembled in the presence of Tvl-S is impaired. As a result, Tvl-S does not support the expression of Class II major histocompatibility complex (MHC) genes. Here, we show that the reason Tvl-S is inactive as a transcriptional regulator of Class II MHC genes is that the RFX complexes assembled in the presence of Tvl-S are unstable. Additionally, we show that interferon-gamma, which induces Class II MHC gene expression in 293 cells, promotes a shift in the splicing pattern of RFXANK/Tvl-1 toward the transcriptionally active Tvl-L isoform, suggesting that differential splicing of Tvl-1 is a signal-regulated process. Finally, we show that Tvl-1 regulates the expression of non-MHC genes. One such gene encodes the ephrin receptor EphA3. Since both Tvl-L and Tvl-S are identical in their ability to induce the expression of EphA3, we conclude that Tvl-1 regulates the expression of non-MHC genes by RFX-independent mechanisms.
Das
Santasabuj
S
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Lin
Jun-Hsiang
JH
Papamatheakis
Joseph
J
Sykulev
Yuri
Y
Tsichlis
Philip N
PN
D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D017089:Ankyrin Repeat; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D046911:Macromolecular Substances; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D036121:Receptor, EphA3 / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009841:Oligonucleotides; D020033:Protein Isoforms; C093524:RFX5 protein, human; C413004:RFXAP protein, human; D000071701:Regulatory Factor X Transcription Factors; C119810:Rfxank protein, mouse; D014157:Transcription Factors; D007371:Interferon-gamma; D036121:Receptor, EphA3