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doi: 10.1242/10.1242/dev.00578

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Development 130, 3459-3468 (2003)
Copyright © 2003 The Company of Biologists Limited

A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland

Ekaterini A. Kritikou1, Andrew Sharkey1, Kathrine Abell1, Paul J. Came1, Elizabeth Anderson2, Richard W. E. Clarkson1 and Christine J. Watson1,*

1 Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
2 Clinical Research Department, Christie Hospital NHS Trust, Manchester M20 4BX, UK

* Author for correspondence (e-mail: cjw53{at}mole.bio.cam.ac.uk)

Accepted 9 April 2003

STAT3 is the key mediator of apoptosis in mammary gland. We demonstrate here that LIF is the physiological activator of STAT3, because in involuting mammary glands of Lif-;/-; mice, pSTAT3 is absent and the STAT3 target, C/EBP{delta}, is not upregulated. Similar to Stat3 knockouts, Lif-;/-; mammary glands exhibit delayed involution, reduced apoptosis and elevated levels of p53. Significantly, Lif-;/-; glands display precocious development during pregnancy, when pSTAT3 is not normally detected. We show that pERK1/2 is significantly reduced in Lif-;/-; glands at this time, suggesting that at this stage LIF mediates its effects through pERK1/2. Inhibition of LIF-mediated ERK1/2 phosphorylation potentiates the proapoptotic effects of STAT3. LIF therefore signals alternately through ERK1/2, then STAT3, to regulate mammary growth and apoptosis.

Key words: LIF, Mammary development, STAT3, Apoptosis, ERK, Mouse


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