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Hodgkin's lymphoma cells express alternatively spliced forms of HDM2 with multiple effects on cell cycle control

Oncogene volume 25, pages 2565–2574 (2006)Cite this article

Abstract

The HDM2 oncoprotein is a cellular inhibitor of p53 and is frequently deregulated in human cancer. However, the HDM2 gene encodes alternatively spliced variants whose functional significance is poorly understood. We had previously reported the detection of alternative HDM2 forms in Hodgkin's lymphoma (HL)-derived cell lines. Here, we have cloned several of these transcripts, including the previously described HDM2-A, -B and -C (which encode the COOH terminus of HDM2), and two novel variants (HDM2-HL1 and -HL2) containing a complete p53 interaction domain. Real-time PCR assays demonstrated that HDM2-A and -B were selectively expressed by HL cell lines and primary tumors, compared with their non-neoplastic counterparts. In transient transfection experiments, alternatively spliced HDM2 isoforms were partially or totally localized within the cytoplasm. HDM2-HL2 was able to inhibit transactivation of a p53-inducible reporter construct and induced a partial relocalization of p53 to the cytoplasm. Expression of HDM2-A and -B caused the activation of p53/p21 and induced growth arrest in primary cells, but also increased the expression levels of cyclins D1 and E. Other possible genes regulated by HDM2-A and -B were identified using cDNA microarray technology. These results imply that HDM2 isoforms may have multiple effects on cell cycle control, and provide insight into the mechanisms through which these molecules contribute to tumorigenesis.

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Acknowledgements

We thank the Tumour Bank Network coordinated by the Molecular Pathology Programme of the CNIO, for providing the tissue samples; members of the Experimental Oncology, Tumor Suppression, and Assay Development groups of the CNIO for reagents and methodological advice; Paloma de la Cueva and Lourdes Romero for excellent technical assistance; and Manuel Serrano for a critical reading of the manuscript.

This work was supported by grants from the Comunidad Autónoma de Madrid (08.1/0042.1/2003), the Ministerio de Ciencia y Tecnología (SAF2001-0060), and the Fondo de Investigaciones Sanitarias (FIS, G03/179). AS-A is supported by a fellowship from the Consejería de Educación de la Comunidad de Madrid and the European Social Fund.

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  1. Lymphoma Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    A Sánchez-Aguilera, J F García, M Sánchez-Beato & M A Piris

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  1. A Sánchez-Aguilera
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Correspondence to A Sánchez-Aguilera.

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Sánchez-Aguilera, A., García, J., Sánchez-Beato, M. et al. Hodgkin's lymphoma cells express alternatively spliced forms of HDM2 with multiple effects on cell cycle control. Oncogene 25, 2565–2574 (2006). https://doi.org/10.1038/sj.onc.1209282

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