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Vol. 15, Issue 4, 1600-1608, April 2004

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Tumor Suppressor Activity of Profilin Requires a Functional Actin Binding Site

Nina Wittenmayer ^*, Burkhard Jandrig , Martin Rothkegel ^*, Kathrin Schlüter ^* , Wolfgang Arnold , Wolfgang Haensch ^||, Siegfried Scherneck , and Brigitte M. Jockusch ^* ¶

^* Cell Biology, Zoological Institute, Technical University of Braunschweig, D-38092 Braunschweig, Germany; Tumor Genetics, Max-Delbrück-Center for Molecular Medicine, D-13092 Berlin-Buch, Germany; atugen AG, D-13125 Berlin-Buch, Germany; and ^|| Clinic of Surgery and Surgical Oncology, Robert Rössle Hospital, D-13122 Berlin-Buch, Germany

Submitted December 5, 2003; Revised January 7, 2004; Accepted January 8, 2004
Monitoring Editor: Thomas Pollard

Profilin 1 (PFN1) is a regulator of the microfilament system and is involved in various signaling pathways. It interacts with many cytoplasmic and nuclear ligands. The importance of PFN1 for human tissue differentiation has been demonstrated by the findings that human cancer cells, expressing conspicuously low PFN1 levels, adopt a nontumorigenic phenotype upon raising their PFN1 level. In the present study, we characterize the ligand binding site crucial for profilin's tumor suppressor activity. Starting with CAL51, a human breast cancer cell line highly tumorigenic in nude mice, we established stable clones that express PFN1 mutants differentially defective in ligand binding. Clones expressing PFN1 mutants with reduced binding to either poly-proline-stretch ligands or phosphatidyl-inositol-4,5-bisphosphate, but with a functional actin binding site, were normal in growth, adhesion, and anchorage dependence, with only a weak tendency to elicit tumors in nude mice, similar to controls expressing wild-type PFN1. In contrast, clones expressing a mutant with severely reduced capacity to bind actin still behaved like the parental CAL51 and were highly tumorigenic. We conclude that the actin binding site on profilin is instrumental for normal differentiation of human epithelia and the tumor suppressor function of PFN1.

Abbreviations used: Arp, actin-related protein; PFN1, profilin 1; PIP2; phospho-inositol-4,5-bisphosphate.

Present address: BD Biosciences, D-69126 Heidelberg, Germany.

^¶ Corresponding author. E-mail address: bmj{at}tu-bs.de.

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