SOLUBLE HYALURONAN RECEPTOR RHAMM INDUCES MITOTIC ARREST BY SUPPRESSING CDC2 AND CYCLIN B1 EXPRESSION

The hyaluronan (HA) receptor RHAMM is an important regulator of cell g rowth. Overexpression of RHAMM is transforming and is required for H-r as transformation. The molecular mechanism underlying growth control b y RHAMM and other extracellular matrix receptors remains largely unkno wn. We report that soluble RHAMM induces G(2)/M arrest by suppressing the expression of Cdc2/Cyclin B1, a protein kinase complex essential f or mitosis. Downregulation of RHAMM by use of dominant negative mutant s or antisense mRNA also decreases Cdc2 protein levels. Suppression of Cdc2 occurs as a result of an increased rate of cdc2 mRNA degradation . Moreover, tumor cells treated with soluble RHAMM are unable to form lung metastases. Thus, we show that mitosis is directly linked to RHAM M through control of Cdc2 and Cyclin B1 expression. Failure to sustain levels of Cdc2 and Cyclin B1 proteins leads to cell cycle arrest.