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Int J Biol Sci 2010; 6(7):700-715. doi:10.7150/ijbs.6.700 This issue Cite

Research Paper

Bone morphogenetic protein 4 (BMP4) signaling in retinoblastoma cells

Maike Haubold¹, Andreas Weise¹, Harald Stephan², Nicole Dünker^{1 ✉}

1. Institute for Anatomy, Department of Neuroanatomy, University of Duisburg-Essen, Medical Faculty, 45122 Essen, Germany
2. Division of Haematology and Oncology, Children's Hospital, University of Duisburg-Essen, 45122 Essen, Germany

✉ Corresponding author: Prof. Dr. Nicole Dünker, Institute for Anatomy, Department of Neuroanatomy, University of Duisburg-Essen, Medical Faculty, 45122 Essen, Germany. Phone: ++49-(0)201-723-4922; fax: ++49-(0)201-723-5635; e-mail: nicole.duenkerde More

Abstract

Bone morphogenetic proteins (BMPs) - expressed in the developing retina - are known to be involved in the regulation of cell proliferation and apoptosis in several tumor entities. The objective of this study was to determine the role of the BMP4 pathway in retinoblastoma cells, which are absent in a functional retinoblastoma (RB1) gene. BMP receptors were detected in all retinoblastoma cell lines investigated. A correct transmission of BMP signaling via the Smad1/5/8 pathway could be demonstrated in WERI-Rb1 retinoblastoma cells and application of recombinant human BMP4 resulted in an increase in apoptosis, which to a large extend is caspase independent. Cell proliferation was not affected by BMP4 signaling, although the pRb-related proteins p107 and p130, contributing to the regulation of the same genes, are still expressed. WERI-Rb1 cells exhibit elevated endogenous levels of p21^CIP1 and p53, but we did not detect any increase in p53, p21^CIP1or p27^KIP1 expression levels. Id proteins became, however, strongly up-regulated upon exogenous BMP4 treatment. Thus, RB1 loss in WERI-Rb1 cells is obviously not compensated for by pRb-independent (e.g. p53-dependent) cell cycle control mechanisms, preventing an anti-proliferative response to BMP4, which normally induces cell cycle arrest.

Keywords: retinoblastoma, apoptosis, proliferation, cell culture, bone morphogenetic protein

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