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The Non-Enzymatic RAS Effector RASSF7 Inhibits Oncogenic c-Myc Function

The Non-Enzymatic RAS Effector RASSF7 Inhibits Oncogenic c-Myc Function

Anbarasu Kumaraswamy, Anitha Mamidi, Pavitra Desai, Ananthi Sivagnanam, Lakshmi Revathi Perumalsamy, Chandrasekaran Ramakrishnan, Michael Gromiha, Krishnaraj Rajalingam, Sundarasamy Mahalingam

J Biol Chem. 2018 Oct 5;293(40):15691-15705.

PMID: 30139745

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42414975	Myc-associated factor X (MAX) human			Price

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