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Molecular and Cellular Biology, March 2003, p. 2109-2122, Vol. 23, No. 6
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.6.2109-2122.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Novel RING Finger Protein, Human Enhancer of Invasion 10, Alters Mitotic Progression through Regulation of Cyclin B Levels

Garabet G. Toby,1,2 Wahiba Gherraby,1 Thomas R. Coleman,1,{dagger} and Erica A. Golemis1*

Division of Basic Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,1 Cell and Molecular Biology Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191042

Received 9 September 2002/ Returned for modification 7 November 2002/ Accepted 30 December 2002

The process of cellular morphogenesis is highly conserved in eukaryotes and is dependent upon the function of proteins that are centrally involved in specification of the cell cycle. The human enhancer of invasion clone 10 (HEI10) protein was identified from a HeLa cell library based on its ability to promote yeast agar invasion and filamentation. Through two-hybrid screening, the mitotic cyclin B1 and an E2 ubiquitin-conjugating enzyme were isolated as HEI10-interacting proteins. Mutation of the HEI10 divergent RING finger motif (characteristic of E3 ubiquitin ligases) and Cdc2/cyclin binding and phosphorylation sites alter HEI10-dependent yeast phenotypes, including delay in G2/M transition. In vertebrates, the addition of HEI10 inhibits nuclear envelope breakdown and mitotic entry in Xenopus egg extracts. Mechanistically, HEI10 expression reduces cyclin B levels in cycling Xenopus eggs and reduces levels of the cyclin B ortholog Clb2p in yeast. HEI10 is itself a specific in vitro substrate of purified cyclin B/cdc2, with a TPVR motif as primary phosphorylation site. Finally, HEI10 is itself ubiquitinated in egg extracts and is also autoubiquitinated in vitro. These and other points lead to a model in which HEI10 defines a divergent class of E3 ubiquitin ligase, functioning in progression through G2/M.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Phone: (215) 728-2860. Fax: (215) 728-3616. E-mail: EA_Golemis{at}fccc.edu.

{dagger} Present address: The Kenneth S. Warren Institute, Ossining, NY 10562.

Molecular and Cellular Biology, March 2003, p. 2109-2122, Vol. 23, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.6.2109-2122.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Einarson, M. B., Cukierman, E., Compton, D. A., Golemis, E. A. (2004). Human Enhancer of Invasion-Cluster, a Coiled-Coil Protein Required for Passage through Mitosis. Mol. Cell. Biol. 24: 3957-3971 [Abstract] [Full Text]  


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