Abstract
Interferon regulatory factor-1 (IRF-1) is a transcription factor and tumor suppressor that can regulate gene expression in a manner requiring either its sequence specific DNA binding activity or its ability to bind the p300 coactivator. We show that IRF-1-mediated growth inhibition is dependent on the integrity of a C-terminal transcriptional enhancer domain. An enhancer subdomain (amino acids 301-325) that differentially regulates IRF-1 activity has been identified and this region mediates the repression of Cdk2. The repressor domain encompasses an LXXLL coregulator signature motif and mutations or deletions within this region completely uncouple transcriptional activation from repression. The loss of growth suppressor activity when the Cdk2-repressor domain of IRF-1 is mutated implicates repression as a determinant of its maximal growth inhibitory potential. The data link IRF-1 regulatory domains to its growth inhibitory activity and provide information about how differential gene regulation may contribute to IRF-1 tumor suppressor activity.
Highlights
Interferon regulatory factor-1 (IRF-1) has been described as a tumor suppressor as its loss can increase susceptibility to transformation by oncogenes (8) and expression of IRF-1 can revert the phenotype of cells transformed with c-Ha-ras or c-myc (9)
The data presented here shed light on how IRF-1 structure and function relate to its growth inhibitory activity and begins to define domains which may be important for IRF-1 mediated tumor suppression
The ability of IRF-1 to inhibit cell growth was assessed in two cell lines with differing p53 status; HCT116 colorectal cancer cells have a well characterized functional p53 pathway (28), whereas H1299 cells are null for p53 (29)
Summary
IRF-1 has been described as a tumor suppressor as its loss can increase susceptibility to transformation by oncogenes (8) and expression of IRF-1 can revert the phenotype of cells transformed with c-Ha-ras or c-myc (9). Based on the observation that enhancer domain mutants of IRF-1 are severely compromised in their ability to suppress cell growth we have identified novel regulatory motifs within the C-terminal 25 amino acids of the protein which are involved in the differential modulation of gene activation and repression.
Sign-in/Register to view highlights & summary 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.
