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Mol. Cell. Biol. doi:10.1128/MCB.00800-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Single and combined ERK1/ERK2 silencing reveals their positive contribution to growth signaling depending on their expression levels

Institute of Signaling Developmental Biology and Cancer, CNRS UMR 6543, Université de Nice Sophia Antipolis, Centre A. Lacassagne, 33 Avenue de Valombrose, 06189 Nice, France

^* To whom correspondence should be addressed. Email: lenorman{at}unice.fr.

	Abstract

The proteins ERK1 and ERK2 are highly similar, ubiquitously expressed and share activators and substrates; however erk2 gene invalidation is lethal in mice while erk1 is not. We ablated ERK1 and/or ERK2 by RNA interference and explored their relative role in cell proliferation and immediate-early genes (IEGs) expression. Reducing expression of either ERK1 or ERK2 lowered IEG induction by serum, however silencing of only ERK2 slowed-down cell proliferation. When both isoforms were silenced simultaneously, compensating activation of the residual pool of ERK1/2 masked a more deleterious effect on cell proliferation. It is only when ERK2 activation was clamped at a limiting level that we demonstrated the positive contribution of ERK1 to cell proliferation. We then established that ERK isoforms are activated indiscriminately, their expression ratio correlated exactly with their activation ratio. Furthermore, we determined for the first time that ERK1 and ERK2 kinase activities are indistinguishable in vitro and that erk gene dosage is essential for survival of mice. We propose that the expression levels of ERK1 and ERK2 drive their apparent biological differences. Indeed, ERK1 is dispensable in some vertebrates since it is absent from chicken and frog genome despite being present in all fishes sequenced so far.

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