Abstract
c-Myc is a proto-oncogene controlling expression of multiple genes involved in cell growth and differentiation. Although the functional role of c-Myc as a transcriptional regulator has been intensively studied, targeting this protein in cancer remains a challenge. Here, we report a trimodal regulation of c-Myc function by the Ras effector, Ras-association domain family member 7 (RASSF7), a nonenzymatic protein modulating protein-protein interactions to regulate cell proliferation. Using HEK293T and HeLa cell lines, we provide evidence that RASSF7 destabilizes the c-Myc protein by promoting Cullin4B-mediated polyubiquitination and degradation. Furthermore, RASSF7 competed with MYC-associated factor X (MAX) in the formation of a heterodimeric complex with c-Myc and attenuated its occupancy on target gene promoters to regulate transcription. Consequently, RASSF7 inhibited c-Myc-mediated oncogenic transformation, and an inverse correlation between the expression levels of the RASSF7 and c-Myc genes was evident in human cancers. Furthermore, we found that RASSF7 interacts with c-Myc via its RA and leucine zipper (LZ) domains and LZ domain peptide is sufficient to inhibit c-Myc function, suggesting that this peptide might be used to target oncogenic c-Myc. These results unveil that RASSF7 and c-Myc are functionally linked in the control of tumorigenesis and open up potential therapeutic avenues for targeting the "undruggable" c-Myc protein in a subset of human cancers.
Highlights
Edited by Alex Toker c-Myc is a proto-oncogene controlling expression of multiple genes involved in cell growth and differentiation
We found that Ras-association domain family member 7 (RASSF7) interacts with c-Myc via its RA and leucine zipper (LZ) domains and LZ domain peptide is sufficient to inhibit c-Myc function, suggesting that this peptide might be used to target oncogenic c-Myc
We first analyzed the expression pattern of genes that are critical for cell cycle regulation such as p21 (CDKN1A), p27 (CDKN1B), and Cdc42 in the presence of RASSF7
Summary
Edited by Alex Toker c-Myc is a proto-oncogene controlling expression of multiple genes involved in cell growth and differentiation. The functional role of c-Myc as a transcriptional regulator has been intensively studied, targeting this protein in cancer remains a challenge. We report a trimodal regulation of c-Myc function by the Ras effector, Ras-association domain family member 7 (RASSF7), a nonenzymatic protein modulating protein– protein interactions to regulate cell proliferation. RASSF7 competed with MYC-associated factor X (MAX) in the formation of a heterodimeric complex with c-Myc and attenuated its occupancy on target gene promoters to regulate transcription. RASSF7 inhibited c-Myc–mediated oncogenic transformation, and an inverse correlation between the expression levels of the RASSF7 and c-Myc genes was evident in human cancers. A distinct class of Ras effectors has been identified known as Ras Association Domain Family of proteins (RASSF) that are. S1–S7, Tables S1 and S2, and Videos S1–S3. 1 To whom correspondence should be addressed: Laboratory of Molecular
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: 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.