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E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

Oncogene volume 19, pages 2887–2894 (2000)Cite this article

Abstract

Squamous differentiation of keratinocytes is associated with decreases in E2F-1 mRNA expression and E2F activity, and these processes are disrupted in squamous cell carcinoma cell lines. We now show that E2F-1 mRNA expression is increased in primary squamous cell carcinomas of the skin relative to normal epidermis. To explore the relationship between E2F-1 and squamous differentiation further, we examined the effect of altering E2F activity in primary human keratinocytes induced to differentiate. Promoter activity for the proliferation-associated genes, cdc2 and keratin 14, are inhibited during squamous differentiation. This inhibition can be inhibited by overexpression of E2F-1 in keratinocytes. Overexpression of E2F-1 also suppressed the expression of differentiation markers (transglutaminase type 1 and keratin 10) in differentiated keratinocytes. Blocking E2F activity by transfecting proliferating keratinocytes with dominant negative E2F-1 constructs inhibited the expression of cdc2 and E2F-1, but did not induce differentiation. Furthermore, expression of the dominant negative construct in epithelial carcinoma cell lines and normal keratinocytes decreased expression from the cdc2 promoter. These data indicate that E2F-1 promotes keratinocyte proliferation-specific marker genes and suppresses squamous differentiation-specific marker genes. Moreover, these data indicate that targeted disruption of E2F-1 activity may have therapeutic potential for the treatment of squamous carcinomas.

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Acknowledgements

This work was supported in part by the Queensland Cancer Fund (# 98/QCFN001G), the Garnett Passe and Rodney Williams Memorial Foundation, the Princess Alexandra Hospital Foundation and the Australian Government Employees Medical Defence Fund. AJ Dicker was supported by a post-graduate scholarship from EMA & MC Henker foundation and the National Health and Medical Research Council. NA Saunders is sponsored by a Lions Medical Research Foundation Senior Research Fellowship and C Popa is supported by an Australian Postgraduate Award. MM Serewko is supported by a postgraduate scholarship awarded by the Garnett Passe and Rodney Williams Memorial Foundation.

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  1. University of Queensland Department of Medicine, Epithelial Pathobiology Group, Centre for Immunology and Cancer Research, Princess Alexandra Hospital, Brisbane, 4102, Queensland, Australia

    Anthony J Dicker, Claudia Popa, Alison L Dahler, Magdelena M Serewko, Paige A Hilditch-Maguire, Ian H Frazer & Nicholas A Saunders

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Dicker, A., Popa, C., Dahler, A. et al. E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes. Oncogene 19, 2887–2894 (2000). https://doi.org/10.1038/sj.onc.1203610

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