The non-enzymatic RAS effector RASSF7 inhibits oncogenic c-Myc function.

Autor:	Kumaraswamy A; From the National Cancer Tissue Biobank, Laboratory of Molecular Cell Biology and., Mamidi A; From the National Cancer Tissue Biobank, Laboratory of Molecular Cell Biology and., Desai P; From the National Cancer Tissue Biobank, Laboratory of Molecular Cell Biology and., Sivagnanam A; From the National Cancer Tissue Biobank, Laboratory of Molecular Cell Biology and., Perumalsamy LR; From the National Cancer Tissue Biobank, Laboratory of Molecular Cell Biology and., Ramakrishnan C; Protein Bioinformatics Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai 600036, India and., Gromiha M; Protein Bioinformatics Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai 600036, India and., Rajalingam K; the MSU-FZI, Institute of Immunology, University Medical Center Mainz, JGU, 55131 Mainz, Germany., Mahalingam S; From the National Cancer Tissue Biobank, Laboratory of Molecular Cell Biology and mahalingam@iitm.ac.in.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2018 Oct 05; Vol. 293 (40), pp. 15691-15705. Date of Electronic Publication: 2018 Aug 23.
DOI:	10.1074/jbc.RA118.004452
Abstrakt:	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. (© 2018 Kumaraswamy et al.)
Databáze:	MEDLINE
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