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In vivo Significance of the G₂ Restriction Point

Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands

Requests for reprints: Hein te Riele, Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands. Phone: 31-20-512-2084; Fax: 31-20-669-1383; E-mail: h.t.riele{at}nki.nl.

Loss of activity of the retinoblastoma pathway is a common event in human cancer. Mouse models have revealed that tumorigenesis by loss of Rb was accelerated by concomitant loss of the cell cycle inhibitor p27^KIP1. This has been attributed to reduced apoptosis and weakening of the G₁ checkpoint. However, the role of p27^KIP1 in a recently identified G₂ restriction point may offer an alternative explanation for this synergy. Here, we have investigated the significance of the G₂ restriction point in Rb-deficient pituitaries. We show that Rb loss in the pituitary gland activated the G₂ restriction point, as evidenced by the appearance of cyclin B1–p27^KIP1 complexes. Somewhat unexpectedly, these complexes remained present in Rb-deficient tumors. These results indicate that the G₂ restriction point does operate in vivo. However, in the pituitary gland, this mechanism seems to retard rather than to prevent tumor growth. [Cancer Res 2007;67(19):9244–7]