Journal article

Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the INK4/ARF locus in non-small cell lung cancer

Cristina Gamell, Twishi Gulati, Yaara Levav-Cohen, Richard J Young, Hongdo Do, Pat Pilling, Elena Takano, Neil Watkins, Stephen B Fox, Prudence Russell, Doron Ginsberg, Brendon J Monahan, Gavin Wright, Alex Dobrovic, Sue Haupt, Ben Solomon, Ygal Haupt

SCIENCE SIGNALING | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2017

Abstract

The tumor suppressor p16INK4a, one protein encoded by the INK4/ARF locus, is frequently absent in multiple cancers, including non-small cell lung cancer (NSCLC). Whereas increased methylation of the encoding gene (CDKN2A) accounts for its loss in a third of patients, no molecular explanation exists for the remainder. We unraveled an alternative mechanism for the silencing of the INK4/ARF locus involving the E3 ubiquitin ligase and transcriptional cofactor E6AP (also known as UBE3A). We found that the expression of three tumor suppressor genes encoded in the INK4/ARF locus (p15INK4b, p16INK4a, and p19ARF) was decreased in E6AP-/- mouse embryo fibroblasts. E6AP induced the expression of the IN..

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Grants

Awarded by National Health and Medical Research Council (NHMRC) of Australia


Awarded by Cancer Council Victoria


Awarded by Victorian Cancer Agency-Richard Pratt Fellowship


Funding Acknowledgements

This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia to Y.H. (NHMRC 1063389 and 1026990), by a grant from the Cancer Council Victoria (1085154), and by the Victorian Endowment for Science, Knowledge, and Innovation award. C.G. was supported by a Victorian Cancer Agency-Richard Pratt Fellowship (Pratt14002).