Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Apr 1;183(4):1663–1668. doi: 10.1084/jem.183.4.1663

Soluble hyaluronan receptor RHAMM induces mitotic arrest by suppressing Cdc2 and cyclin B1 expression

PMCID: PMC2192524  PMID: 8666924

Abstract

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.

Full Text

The Full Text of this article is available as a PDF (805.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bartolazzi A., Peach R., Aruffo A., Stamenkovic I. Interaction between CD44 and hyaluronate is directly implicated in the regulation of tumor development. J Exp Med. 1994 Jul 1;180(1):53–66. doi: 10.1084/jem.180.1.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brecht M., Mayer U., Schlosser E., Prehm P. Increased hyaluronate synthesis is required for fibroblast detachment and mitosis. Biochem J. 1986 Oct 15;239(2):445–450. doi: 10.1042/bj2390445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burridge K., Turner C. E., Romer L. H. Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. J Cell Biol. 1992 Nov;119(4):893–903. doi: 10.1083/jcb.119.4.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Clark E. A., Brugge J. S. Integrins and signal transduction pathways: the road taken. Science. 1995 Apr 14;268(5208):233–239. doi: 10.1126/science.7716514. [DOI] [PubMed] [Google Scholar]
  6. Dalton S. Cell cycle regulation of the human cdc2 gene. EMBO J. 1992 May;11(5):1797–1804. doi: 10.1002/j.1460-2075.1992.tb05231.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Egan S. E., Wright J. A., Jarolim L., Yanagihara K., Bassin R. H., Greenberg A. H. Transformation by oncogenes encoding protein kinases induces the metastatic phenotype. Science. 1987 Oct 9;238(4824):202–205. doi: 10.1126/science.3659911. [DOI] [PubMed] [Google Scholar]
  8. Greenberg M. E., Ziff E. B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature. 1984 Oct 4;311(5985):433–438. doi: 10.1038/311433a0. [DOI] [PubMed] [Google Scholar]
  9. Guadagno T. M., Ohtsubo M., Roberts J. M., Assoian R. K. A link between cyclin A expression and adhesion-dependent cell cycle progression. Science. 1993 Dec 3;262(5139):1572–1575. doi: 10.1126/science.8248807. [DOI] [PubMed] [Google Scholar]
  10. Hall C. L., Wang C., Lange L. A., Turley E. A. Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity. J Cell Biol. 1994 Jul;126(2):575–588. doi: 10.1083/jcb.126.2.575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hall C. L., Yang B., Yang X., Zhang S., Turley M., Samuel S., Lange L. A., Wang C., Curpen G. D., Savani R. C. Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell. 1995 Jul 14;82(1):19–26. doi: 10.1016/0092-8674(95)90048-9. [DOI] [PubMed] [Google Scholar]
  12. Han E. K., Guadagno T. M., Dalton S. L., Assoian R. K. A cell cycle and mutational analysis of anchorage-independent growth: cell adhesion and TGF-beta 1 control G1/S transit specifically. J Cell Biol. 1993 Jul;122(2):461–471. doi: 10.1083/jcb.122.2.461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hardwick C., Hoare K., Owens R., Hohn H. P., Hook M., Moore D., Cripps V., Austen L., Nance D. M., Turley E. A. Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J Cell Biol. 1992 Jun;117(6):1343–1350. doi: 10.1083/jcb.117.6.1343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kornberg L. J., Earp H. S., Turner C. E., Prockop C., Juliano R. L. Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8392–8396. doi: 10.1073/pnas.88.19.8392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Laurent T. C., Fraser J. R. Hyaluronan. FASEB J. 1992 Apr;6(7):2397–2404. [PubMed] [Google Scholar]
  16. Lee M. G., Norbury C. J., Spurr N. K., Nurse P. Regulated expression and phosphorylation of a possible mammalian cell-cycle control protein. Nature. 1988 Jun 16;333(6174):676–679. doi: 10.1038/333676a0. [DOI] [PubMed] [Google Scholar]
  17. McGowan C. H., Russell P., Reed S. I. Periodic biosynthesis of the human M-phase promoting factor catalytic subunit p34 during the cell cycle. Mol Cell Biol. 1990 Jul;10(7):3847–3851. doi: 10.1128/mcb.10.7.3847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pilarski L. M., Miszta H., Turley E. A. Regulated expression of a receptor for hyaluronan-mediated motility on human thymocytes and T cells. J Immunol. 1993 May 15;150(10):4292–4302. [PubMed] [Google Scholar]
  19. Pines J., Hunter T. Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell. 1989 Sep 8;58(5):833–846. doi: 10.1016/0092-8674(89)90936-7. [DOI] [PubMed] [Google Scholar]
  20. Riabowol K., Draetta G., Brizuela L., Vandre D., Beach D. The cdc2 kinase is a nuclear protein that is essential for mitosis in mammalian cells. Cell. 1989 May 5;57(3):393–401. doi: 10.1016/0092-8674(89)90914-8. [DOI] [PubMed] [Google Scholar]
  21. Samuel S. K., Hurta R. A., Spearman M. A., Wright J. A., Turley E. A., Greenberg A. H. TGF-beta 1 stimulation of cell locomotion utilizes the hyaluronan receptor RHAMM and hyaluronan. J Cell Biol. 1993 Nov;123(3):749–758. doi: 10.1083/jcb.123.3.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Savani R. C., Wang C., Yang B., Zhang S., Kinsella M. G., Wight T. N., Stern R., Nance D. M., Turley E. A. Migration of bovine aortic smooth muscle cells after wounding injury. The role of hyaluronan and RHAMM. J Clin Invest. 1995 Mar;95(3):1158–1168. doi: 10.1172/JCI117764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shi L., Nishioka W. K., Th'ng J., Bradbury E. M., Litchfield D. W., Greenberg A. H. Premature p34cdc2 activation required for apoptosis. Science. 1994 Feb 25;263(5150):1143–1145. doi: 10.1126/science.8108732. [DOI] [PubMed] [Google Scholar]
  24. Sy M. S., Guo Y. J., Stamenkovic I. Inhibition of tumor growth in vivo with a soluble CD44-immunoglobulin fusion protein. J Exp Med. 1992 Aug 1;176(2):623–627. doi: 10.1084/jem.176.2.623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Th'ng J. P., Wright P. S., Hamaguchi J., Lee M. G., Norbury C. J., Nurse P., Bradbury E. M. The FT210 cell line is a mouse G2 phase mutant with a temperature-sensitive CDC2 gene product. Cell. 1990 Oct 19;63(2):313–324. doi: 10.1016/0092-8674(90)90164-a. [DOI] [PubMed] [Google Scholar]
  26. Turley E. A., Belch A. J., Poppema S., Pilarski L. M. Expression and function of a receptor for hyaluronan-mediated motility on normal and malignant B lymphocytes. Blood. 1993 Jan 15;81(2):446–453. [PubMed] [Google Scholar]
  27. Welch P. J., Wang J. Y. Coordinated synthesis and degradation of cdc2 in the mammalian cell cycle. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3093–3097. doi: 10.1073/pnas.89.7.3093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Yang B., Zhang L., Turley E. A. Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM. J Biol Chem. 1993 Apr 25;268(12):8617–8623. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES