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- Title
- Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif
- Author/Creator
-
Darnell, G A |
Antalis, T M |
Johnstone, R W |
Stringer, B W |
Ogbourne, S |
Harrich, D |
Suhrbier, A
- Description
- 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.
- Relation
- Molecular and Cellular Biology / Vol. 23, No. 18, pp.6520-6532
- Relation
- http://mcb.asm.org/
- Year
- 2003
- Publisher
- American Society for Microbiology
- Subject
-
FoR 06 (Biological Sciences) |
FoR 11 (Medical and Health Sciences)
- Collection(s)
- Research Publications
- Resource Type
- Journal Article
- Identifier
- ISSN: 0270-7306
- Reviewed

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