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Molecular and Cellular Biology, June 2002, p. 3717-3728, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3717-3728.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cyclic AMP Blocks Cell Growth through Raf-1-Dependent and Raf-1-Independent Mechanisms

Nicolas Dumaz, Yvonne Light, and Richard Marais*

Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom

Received 1 November 2001/ Returned for modification 13 December 2001/ Accepted 2 March 2002

It is widely accepted that cyclic AMP (cAMP) can block cell growth by phosphorylating Raf-1 on serine 43 and inhibiting signaling to extracellular signal-regulated protein kinase. We show that the suppression of Raf-1 by cAMP is considerably more complex than previously reported. When cellular cAMP is elevated, Raf-1 is phosphorylated on three residues (S43, S233, and S259), which work independently to block Raf-1. Both Ras-dependent and Ras-independent processes are disrupted. However, when cAMP-insensitive versions of Raf-1 are expressed in NIH 3T3 cells, their growth is still strongly suppressed when cAMP is elevated. Thus, although Raf-1 appears to be an important cAMP target, other pathways are also targeted by cAMP, providing alternative mechanisms that lead to suppression of cell growth.

* Corresponding author. Mailing address: Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, United Kingdom. Phone: 020 7878 3856. Fax: 020 7352 3299. E-mail: rmarais{at}icr.ac.uk.

Molecular and Cellular Biology, June 2002, p. 3717-3728, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3717-3728.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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