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Molecular and Cellular Biology, September 2003, p. 6520-6532, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6520-6532.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif

Grant A. Darnell,1 Toni M. Antalis,2* Ricky W. Johnstone,3 Brett W. Stringer,4 Steven M. Ogbourne,4 David Harrich,5 and Andreas Suhrbier1*

Australian National Centre for International and Tropical Health and Nutrition,1 Experimental Oncology Program, Queensland Institute of Medical Research and University of Queensland,4 Sir Albert Sakzewski Virus Research Centre, Royal Children's Hospital, Brisbane, Queensland 4029,5 and The Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002, Australia,2 Department of Vascular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 208553

Received 21 April 2003/ Returned for modification 21 May 2003/ Accepted 10 June 2003

Plasminogen activator inhibitor-2 (PAI-2) is well documented as an inhibitor of the extracellular serine proteinase urokinase-type plasminogen activator (uPA) and is expressed in activated monocytes and macrophages, differentiating keratinocytes, and many tumors. Here we show that PAI-2 has a novel intracellular function as a retinoblastoma protein (Rb)-binding protein. PAI-2 colocalized with Rb in the nucleus and inhibited the turnover of Rb, which led to increases in Rb protein levels and Rb-mediated activities. Although PAI-2 contains an LXCXE motif, Rb binding was primarily mediated by the C-D interhelical region of PAI-2, which was found to bind to the C pocket of Rb. The C-D interhelical region of PAI-2 contained a novel Rb-binding motif, termed the PENF homology motif, which is shared by many cellular and viral Rb-binding proteins. PAI-2 expression also protected Rb from the accelerated degradation mediated by human papillomavirus (HPV) E7, leading to recovery of Rb and inhibition of E6/E7 mRNA expression. Protection of Rb by PAI-2 begins to explain many of the diverse, uPA-independent phenotypes conferred by PAI-2 expression. These results indicate that PAI-2 may enhance Rb's tumor suppressor activity and suggest a potential therapeutic role for PAI-2 against HPV-transformed lesions.

* Corresponding author. Mailing address for Andreas Suhrbier: Queensland Institute of Medical Research, 300 Herston Rd., Herston, Queensland 4029, Australia. Phone: 61-7-33620415. Fax: 61-7-33620107. E-mail: andreasS{at}qimr.edu.au. Mailing address for Toni M. Antalis: Department of Vascular Biology, Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855. Phone: (301) 738-0658. Fax: (301) 738-0465. E-mail: antalist{at}usa.redcross.org.

Molecular and Cellular Biology, September 2003, p. 6520-6532, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6520-6532.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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