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Molecular and Cellular Biology, November 1999, p. 7529-7538, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Yeast Ras/Cyclic AMP Pathway Induces Invasive Growth by Suppressing the Cellular Stress Response

Ariel Stanhill, Naomi Schick, and David Engelberg*

Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

Received 26 March 1999/Returned for modification 17 May 1999/Accepted 9 August 1999

Haploid yeast cells are capable of invading agar when grown on rich media. Cells of the Sigma 1278b genetic background manifest this property, whereas other laboratory strains are incapable of invasive growth. We show that disruption of the RAS2 gene in the Sigma 1278b background significantly reduces invasive growth but that expression of a constitutively active Ras2p (Ras2Val19p) in this strain has a minimal effect on its invasiveness. On the other hand, expression of Ras2Val19p in another laboratory strain, SP1, rendered it invasive. These results suggest that a hyperactive Ras2 pathway induces invasive growth and that this pathway might be overactive in the Sigma 1278b genetic background. Indeed, cells of the Sigma 1278b are defective in the induction of stress-responsive genes, while their Gcn4 target genes are constitutively transcribed. This pattern of gene expression was previously shown to be associated with an active Ras/cyclic AMP (cAMP) pathway. We show that suppression of stress-related genes in Sigma 1278b cells is a result of their inability to activate transcription through the stress response element (STRE). Disruption of RAS2, which abolished invasiveness, induced an increase in STRE activity. Further, in the SP1 genetic background, disruption of either the MSN2/4 genes (encoding activators of STRE) or the yAP-1 gene was sufficient to restore invasive growth in ras2Delta cells. We conclude that Ras2-mediated suppression of the stress response is sufficient to induce invasiveness. Accordingly, the fact that the stress response is suppressed in Sigma 1278b background explains its invasiveness. It seems that invasiveness is a phenotype related to unregulated growth and is therefore manifested by cells harboring an overactive Ras/cAMP cascade. In this respect, invasiveness in yeast is reminiscent of the property of ras-transformed fibroblasts to invade soft agar.

* Corresponding author. Mailing address: Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Phone: 972 2 6584718. Fax: 972 2 6586448. E-mail: engelber{at}vms.huji.ac.il.

Molecular and Cellular Biology, November 1999, p. 7529-7538, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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