1. Institut für Biochemie, Aachen, Germany
2. ^*Institut für Pathologie, Universität Regensburg, Regensburg, Germany

Correspondence: Iris Behrmann, Laboratoire de Biologie et Physiologie Intégrée, Fac. Sciences, Luxembourg, 162A, avenue de la Faïencerie, 1511 Luxembourg, Techno. & Com., Université du Luxembourg. Email. iris.behrmann@univ.lu

¹Present address: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

²Present address: Laboratoire de Biologie et Physiologie Intégrée, Fac. Sciences, Techo. & Com., Université du Luxembourg, 1511 Luxembourg, Luxembourg.

Received 15 October 2002; Revised 4 August 2003; Accepted 2 September 2003.

Abstract

Interferon-, a known inhibitor of tumor cell growth, has been used in several protocols for the treatment of melanoma. We have studied the molecular events underlying interferon--induced G₀/G₁ arrest in four metastatic melanoma cell lines with different responsiveness to interferon-. The growth arrest did not result from enhanced expression of cyclin-dependent kinase inhibitors p21 and p27. Instead, it correlated with downregulation of cyclin E and cyclin A and inhibition of their associated kinase activities. We show that interferon--induced growth inhibition could be abrogated by overexpression of dominant negative STAT1 (signal transducer and activator of transcription 1) in the melanoma cell line A375, suggesting that STAT1 plays a crucial part for the anti-proliferative effect. Erythropoietin stimulation of a chimeric receptor led to a concentration-dependent STAT1 activation and concomitant growth arrest when it contained the STAT recruitment motif Y440 of the interferon- receptor 1. In contrast, dose–response studies for interferon- revealed a discrepancy between levels of STAT1 activation and the extent of growth inhibition; whereas STAT1 was activated by low doses of interferon- (10 U per mL), growth inhibitory effects were only visible with 100-fold higher concentrations. Our results suggest the presence of additional signals emanating from the interferon- receptor, which may counteract the anti-proliferative function of STAT1.