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 growth. Overexpression of RHAMM is transforming and is required for H-ras transformation. The molecular mechanism underlying growth control by RHAMM and other extracellular matrix receptors remains largely unknown. We report that soluble RHAMM induces G2/M arrest by suppressing the expression of Cdc2/Cyclin B1, a protein kinase complex essential for mitosis. Down-regulation of RHAMM by use of dominant negative mutants or antisense of 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 RHAMM through control of Cdc2 and Cyclin B1 expression. Failure to sustain levels of Cdc2 and Cyclin B1 proteins leads to cell cycle arrest.
Mohapatra
S
S
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada.
Yang
X
X
Wright
J A
JA
Turley
E A
EA
Greenberg
A H
AH
D000818:Animals; D016203:CDC2 Protein Kinase / Q000096:biosynthesis*; D002277:Carcinoma; D002460:Cell Line; D019926:Cyclin B; D056744:Cyclin B1; D016213:Cyclins / Q000096:biosynthesis*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005354:Fibrosarcoma; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000235:genetics; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000556:secondary; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D014407:Tumor Cells, Cultured
C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D016213:Cyclins; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D011993:Recombinant Fusion Proteins; C098946:hyaluronan-mediated motility receptor; D006820:Hyaluronic Acid; D005982:Glutathione Transferase; D016203:CDC2 Protein Kinase