1. ¹Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
2. ²Department of Human Pathology and Oncology University of Siena, Siena, Italy
3. ³Department of Oncology, University of Palermo, Section of Oncology, Palermo, Italy
4. ⁴Institute of General Pathology-Giovanni XXIII Cancer Research Center, Catholic University of Sacred Heart, Roma, Italy
5. ⁵Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
6. ⁶Department of Ophthalmology and Neurosurgery, University of Siena, Italy
7. ⁷Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA

Correspondence: M Macaluso, Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, College of Science and Technology, Temple University, 19122-Philadelphia, PA, USA. Tel: +1 215 204 9520; Fax: +1 215 204 9519; E-mail: macaluso@temple.edu; M Massaro-Giordano, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; E-mail: mina@uphs.upenn.edu

Received 23 June 2005; Revised 2 November 2005; Accepted 3 November 2005; Published online 6 January 2006.

Abstract

Extracellular plasminogen activator inhibitor type-2 (PAI-2) is a potent inhibitor of urokinase-type plasminogen activator (u-PA) and also acts as a multifunctional protein. However, the biological activity of intracellular PAI-2, as well as its intracellular targets, until now remain an enigma. Here, we show that pRb2/p130 and Rb1/p105, but not p107, interact with PAI-2 in both the cytoplasm and nucleus of normal primary human corneal and conjunctival epithelial cells. We provided the first in vivo evidence that a specific fragment of the PAI-2 promoter is bound simultaneously by pRb2/ p130, PAI-2, E2F5, histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1), and histone methyltransferase (SUV39H1), in normal primary human corneal epithelial cells, and by pRb2/p130, PAI-2, E2F5, HDAC1, and DNMT1, in normal primary human conjunctiva epithelial cells. Our results strongly indicate a physiological interaction between pRb family members and PAI-2, suggesting the hypothesis that pRb2/p130 and PAI-2 may cooperate in modulating PAI-2 gene expression by chromatin remodeling, in normal corneal and conjunctival cells.