Abstract
BackgroundHIP1 Protein Interactor (HIPPI) is a pro-apoptotic protein that induces Caspase8 mediated apoptosis in cell. We have shown earlier that HIPPI could interact with a specific 9 bp sequence motif, defined as the HIPPI binding site (HBS), present in the upstream promoter of Caspase1 gene and regulate its expression. We also have shown that HIPPI, without any known nuclear localization signal, could be transported to the nucleus by HIP1, a NLS containing nucleo-cytoplasmic shuttling protein. Thus our present work aims at the investigation of the role of HIPPI as a global transcription regulator.ResultsWe carried out genome wide search for the presence of HBS in the upstream sequences of genes. Our result suggests that HBS was predominantly located within 2 Kb upstream from transcription start site. Transcription factors like CREBP1, TBP, OCT1, EVI1 and P53 half site were significantly enriched in the 100 bp vicinity of HBS indicating that they might co-operate with HIPPI for transcription regulation. To illustrate the role of HIPPI on transcriptome, we performed gene expression profiling by microarray. Exogenous expression of HIPPI in HeLa cells resulted in up-regulation of 580 genes (p < 0.05) while 457 genes were down-regulated. Several transcription factors including CBP, REST, C/EBP beta were altered by HIPPI in this study. HIPPI also interacted with P53 in the protein level. This interaction occurred exclusively in the nuclear compartment and was absent in cells where HIP1 was knocked down. HIPPI-P53 interaction was necessary for HIPPI mediated up-regulation of Caspase1 gene. Finally, we analyzed published microarray data obtained with post mortem brains of Huntington's disease (HD) patients to investigate the possible involvement of HIPPI in HD pathogenesis. We observed that along with the transcription factors like CREB, P300, SREBP1, Sp1 etc. which are already known to be involved in HD, HIPPI binding site was also significantly over-represented in the upstream sequences of genes altered in HD.ConclusionsTaken together, the results suggest that HIPPI could act as an important transcription regulator in cell regulating a vast array of genes, particularly transcription factors and at least, in part, play a role in transcription deregulation observed in HD.
Highlights
Huntingtin Interacting Protein 1 (HIP1) Protein Interactor (HIPPI) is a pro-apoptotic protein that induces Caspase8 mediated apoptosis in cell
HIP1 Protein Interactor (HIPPI) interacts with HIP1 through its pseudo death effector domain and the resulting heterodimer recruits Procaspase8 and activates it thereby inducing Caspase8mediated apoptosis [1]
We found that among the up-regulated genes, 342 genes contained HIPPI binding site (HBS) within 10 Kb upstream sequence and they were enriched in molecular functions like RNA polymerase II transcription factor activity (GO:0003702), transcription factor activity, (GO:0003700) and biological processes like regulation of transcription (GO:0045449) (Additional file 6)
Summary
HIP1 Protein Interactor (HIPPI) is a pro-apoptotic protein that induces Caspase mediated apoptosis in cell. We have shown earlier that HIPPI could interact with a specific 9 bp sequence motif, defined as the HIPPI binding site (HBS), present in the upstream promoter of Caspase gene and regulate its expression. Our present work aims at the investigation of the role of HIPPI as a global transcription regulator. HIPPI interacts with HIP1 through its pseudo death effector domain (pDED) and the resulting heterodimer recruits Procaspase and activates it thereby inducing Caspase8mediated apoptosis [1]. The protein lacks any conventional DNA binding domain, it is shown to interact in vitro and in vivo with a specific 9 bp DNA sequence 5’AAAGACATG-3’ present at the putative promoter of Caspase gene and positively regulate its transcription. Using various variants of the motif, we observed that HIPPI binds with the motif (AAAGA[G/C]A[A/C/T][T/ G]) [5,6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
