The ubiquitin ligase UBE3A dampens ERK pathway signalling in HPV E6 transformed HeLa cells

PloS One
Elisa Aguilar-MartinezAndrew D Sharrocks

Abstract

Signalling through the ERK MAP kinase pathway plays an important role in many biological processes and it is often deregulated in disease states such as cancer. One major effect of MAP kinase signalling is to promote gene expression through the phosphorylation and activation of transcription factors like ELK1. ELK1 in turn controls the activity of immediate-early genes such as FOS. Here we have used ELK1 activation in HeLa cells as a read out to conduct a genome-wide siRNA screen to identify negative regulators of ERK-mediated immediate-early gene activation. One of the candidates that we identified was the E3 ubiquitin ligase UBE3A/E6-AP. Reductions in UBE3A levels cause increased basal levels of ERK activity, a loss of growth factor-mediated ERK activation and concomitant defects in immediate-early gene expression. Thus, UBE3A acts to dampen down basal level ERK activation and to prime the pathway for growth factor-mediated activation. Mechanistically, we demonstrate that UBE3A functions in HeLa cells through its binding partner, HPV18 E6 protein and the E6 target protein p53. Loss of either E6 or p53 blocks the effect of UBE3A depletion on ERK pathway signalling, indicating that in the context of oncogenic viral protein expr...Continue Reading

References

Mar 1, 1992·Molecular and Cellular Biology·R H ChenJ Blenis
Dec 31, 1997·The Journal of Biological Chemistry·T SugimotoK L Guan
Jul 13, 2000·Proceedings of the National Academy of Sciences of the United States of America·S W LeeS A Aaronson
Jul 31, 2003·Molecular Cell·Shen-Hsi YangAndrew D Sharrocks
Mar 3, 2004·Molecular Cell·Shen-Hsi Yang, Andrew D Sharrocks
May 15, 2007·Oncogene·A S DhillonW Kolch
Aug 1, 2008·Cellular and Molecular Life Sciences : CMLS·M Krishna, H Narang
Jan 21, 2012·Biochemical Society Transactions·Amanda O'DonnellAndrew D Sharrocks
Nov 6, 2012·Gene·Shen-Hsi YangAlan J Whitmarsh
Jan 18, 2014·Learning & Memory·Irina FilonovaEdwin J Weeber

Citations

Apr 6, 2018·International Journal of Molecular Sciences·Sara GuzzettiSilvia Russo
Dec 24, 2019·Journal of Neuroscience Research·Xin Yang

Related Concepts

E6 protein, Human papillomavirus type 18
E6 protein, Human papillomavirus type 16
UBE3A protein, human
ELK1 protein, human
Ube3a protein, mouse
Metazoa
Cell Transformation, Viral
DNA Helix Destabilizing Proteins
Enzyme Activation
HeLa Cells

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