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The retinoblastoma-related Rb2/p130 gene is an effector downstream of AP-2 during neural differentiation

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Abstract

Rb2/p130, a member of the Retinoblastoma family of growth and tumour suppressor genes, is extensively implicated in the control of cell cycle and differentiation. The minimal promoter region of Rb2/p130 in T98G human glioblastoma cells was identified and its analysis revealed the presence of a KER1 palindromic sequence able to bind the transcription factor AP-2, a regulatory protein that plays a crucial role in ectodermal differentiation. This KER1 site interacted in vitro with AP-2, and AP-2 overexpression increased Rb2/p130 transcription and translation. We also found that rat PC12 pheochromocytoma cells, when induced to differentiate by NGF, displayed an increase of AP-2 protein levels and of Rb2/p130 transcription and protein levels. AP-2-transfected PC12 cells displayed enhanced transcription and translation of Rb2/p130 and of the cdk inhibitor p21WAF1/CIP1, a gene known to be under the control of AP-2, but unable by itself to elicit PC12 differentiation. Overexpression of either AP-2 or Rb2/p130 elicited per se cell differentiation in the absence of NGF, while coexpression of AP-2B, a negative regulator of AP-2 transcriptional activity, inhibited only AP-2-induced differentiation. Altogether, these results indicate that Rb2/p130 is a critical effector of AP-2 in sustaining ectodermal differentiation.

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Abbreviations

CAT:

chloramphenicol acetyltransferase

EMSA:

electrophoretic mobility shift assay

SDS–PAGE:

polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate

S.D.:

Standard Deviation.

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Acknowledgements

The Authors thank Drs PG Natali, O Segatto, R Tecce (deceased), G Piaggio, A De Luca, M Cippitelli, P Russo, E Palescandolo (Istituto Regina Elena, Rome, Italy) and C Vesco (CNR, Rome) for useful suggestions and criticism, Dr MA Tainsky (Wayne State University, Detroit, MI, USA) for the gift of AP-2 and AP-2B expression plasmids and Dr D Mercanti (CNR, Istituto di Neurobiologia, Rome, Italy) for kindly providing NGF. This work was supported in part by AIRC grants to MG Paggi and A Felsani, by Ministero della Sanità grants to MG Paggi, A Felsani and D Lombardi and by NIH grants RO1 CA 60999-01A1 and PO1 NS 36466 and in part by the Sbarro Institute for Molecular Medicine to A Giordano. F Bonetto and A Baldi were supported by a FIRC post-doctoral fellowship. F Bucci was supported by a CNR fellowship.

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Authors and Affiliations

  1. Laboratory of Cell Metabolism and Pharmacokinetics, Centre for Experimental Research, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, Rome, 00158, Italy

    Marco G Paggi, Francesco Bonetto, Anna Severino, Alfonso Baldi & Tullio Battista

  2. CNR, Istituto Tecnologie Biomediche, Viale Marx 43, Rome, 00137, Italy

    Federica Bucci & Armando Felsani

  3. Department of Experimental Medicine, University of L'Aquila, Via Vetoio, Coppito 2, L'Aquila, 67100, Italy

    Daniela Lombardi

  4. Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, 1020 Locust Street, Philadelphia, 19107, Pennsylvania, PA, USA

    Alfonso Baldi & Antonio Giordano

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  1. Marco G Paggi
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  2. Francesco Bonetto
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  3. Anna Severino
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  4. Alfonso Baldi
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  8. Daniela Lombardi
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Paggi, M., Bonetto, F., Severino, A. et al. The retinoblastoma-related Rb2/p130 gene is an effector downstream of AP-2 during neural differentiation. Oncogene 20, 2570–2578 (2001). https://doi.org/10.1038/sj.onc.1204356

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  • DOI: https://doi.org/10.1038/sj.onc.1204356

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