A Duensing

A Ruiz i Altaba

AJ Olaharski

AM Snijders

B Zhivotovsky

C Mantel

C Tse

CE Jefford

D Duelli

D Hanahan

D Janisson-Dargaud

D Lodygin

D Zhang

DA Nelson

DP Lane

E Gemenetzidis

E Kump

EC Pavarino

EH Epstein

EW Wilker

F Borel

G Regl

GR Ribeiro

H Deng

H Hermeking

H Rajagopalan

I Vitale

J Ji

JA Sterling

JC Strefford

Jo Vandesompele

JS Lanni

K Fukasawa

KJ Ashton

L O'Driscoll

M Castedo

M Grachtchouk

M Hirotsu

M Lobrich

M Tojo

M Vogler

MA Dickson

ME Hutchin

MS Ikram

MT Teh

NJ Ganem

P Erb

PA Beachy

PC Galipeau

PR Andreassen

Q Shi

RL Margolis

S Dhar

S Thiyagarajan

SJ Miller

SL Thompson

SS Jayaraman

T Fujiwara

T Mazumdar

VI Alexaki

X Mao

Y Jin

Z Storchova

ZA Stewart

Cell Death and Disease

Pantazi, E

Gemenetzidis, E

Trigiante, G

Warnes, G

Shan, L

Mao, X

Ikram, M

Teh, M-T

Lu, Y-J

Philpott, MP

Queen Mary Research Online

GLI2 induces genomic instability in human keratinocytes by inhibiting apoptosis

AbstractAbnormal Sonic Hedgehog signalling leads to increased transcriptional activation of its downstream effector, glioma 2 (GLI2), which is implicated in the pathogenesis of a variety of human cancers. However, the mechanisms underlying the tumorigenic role of GLI2 remain elusive. We demonstrate that overexpression of GLI2-β isoform, which lacks the N-terminal repressor domain (GLI2ΔN) in human keratinocytes is sufficient to induce numerical and structural chromosomal aberrations, including tetraploidy/aneuploidy and chromosomal translocations. This is coupled with suppression of cell cycle regulators p21WAF1/CIP1 and 14-3-3σ, and strong induction of anti-apoptotic signalling, resulting in a reduction in the ability to eliminate genomically abnormal cells. Overexpression of GLI2ΔN also rendered human keratinocytes resistant to UVB-mediated apoptosis, whereas inhibition of B-cell lymphoma 2 (BCL-2) restored endogenous (genomic instability (GIN)) and exogenous (UVB) DNA damage-induced apoptosis. Thus, we propose that ectopic expression of GLI2 profoundly affects the genomic integrity of human epithelial cells and contributes to the survival of progenies with genomic alterations by deregulating cell cycle proteins and disabling the apoptotic mechanisms responsible for their elimination. This study reveals a novel role for GLI2 in promoting GIN, a hallmark of human tumors, and identifies potential mechanisms that may provide new opportunities for the design of novel forms of cancer therapeutic strategies.</jats:p

E Pantazi

G Trigiante

G Warnes

L Shan

M Ikram

M-T Teh

Y-J Lu

M P Philpott

Crossref

https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/11129/Teh%20GLI2%20induces%20genomic%20instability%20in%20human%20keratinocytes%20by%20inhibiting%20apoptosis%202014%20Published.pdf?sequence=1

GLI2 induces genomic instability in human keratinocytes by inhibiting apoptosis

Abstract

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Queen Mary Research Online

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