Regulation of cell proliferation by the OGF-OGFr axis is dependent on nuclear localizati...( This release is available in A HREF h...)

Researchers at The Pennsylvania State University College of Medicine, Hershey, Pennsylvania have discovered that the efficacy of the Opioid Growth Factor (OGF, [Met5]-enkephalin), a clinically important antitumor agent, is dependent on nucleocytoplasmic translocation and reliant on the integrity of nuclear localization signals in the OGF receptor (OGFr). This discovery, reported in the May 09 issue of Experimental Biology and Medicine, provides new insights into the mechanism of an important endogenous system that serves as a tonically active, constitutively expressed, inhibitory regulator of DNA synthesis. This valuable information not only may contribute to understanding the etiology and pathogenesis of diseases related to this native biological system, but to the development of new agents that will enhance effectiveness in treatment.

Previous immunohistochemical and immunoelectron microscope studies have detected OGF and OGFr in both the cytoplasmic and the nuclear compartments. The OGF-OGFr axis is known to regulate cell proliferation by modulating cyclin dependent kinase inhibitors, resulting in a retardation of cells at the G1-S interface of the cell cycle. To address the question of the location and temporal relationships of OGFr nucleocytoplasmic trafficking, a probe of OGFr fused to green fluorescent protein (eGFP) was constructed. Experiments with a human cancer cell, a squamous cell carcinoma of the head and neck, revealed that translation of OGFr required approximately 5 hours, and transit into the nucleus took 8 hours; OGFr remained in the nucleus for up to 8 days. Transport through the nuclear pore and repression of cell proliferation required two of the three nuclear localization signals (NLS) in OGFr. These results show that the pathway for regulating the cell cycle by the O
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