E2F modulates keratinocyte squamous differentiation. Implications for E2F inhibition in squamous cell carcinoma

Wong, Chung Fai, Barnes, Liam M., Dahler, Alison L., Smith, Louis, Auret, Magdalena M. Serewko, Popa, Claudia, Abdul Jabbar, Ibtissam and Saunders, Nicholas A. (2003) E2F modulates keratinocyte squamous differentiation. Implications for E2F inhibition in squamous cell carcinoma. Journal of Biological Chemistry, 278 31: 28516-28522. doi:10.1074/jbc.M301246200

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Author Wong, Chung Fai
Barnes, Liam M.
Dahler, Alison L.
Smith, Louis
Auret, Magdalena M. Serewko
Popa, Claudia
Abdul Jabbar, Ibtissam
Saunders, Nicholas A.
Title E2F modulates keratinocyte squamous differentiation. Implications for E2F inhibition in squamous cell carcinoma
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2003
Sub-type Article (original research)
DOI 10.1074/jbc.M301246200
Open Access Status File (Publisher version)
Volume 278
Issue 31
Start page 28516
End page 28522
Total pages 7
Editor Herbert Tabor
Place of publication Bethesda
Publisher American Society for Biochemistry and Molecular Biology, Inc.
Collection year 2003
Language eng
Subject C1
320602 Cell Physiology
730108 Cancer and related disorders
Abstract E2F regulation is essential for normal cell cycle progression. Therefore, it is not surprising that squamous cell carcinoma cell lines (SCC) overexpress E2F1 and exhibit deregulated E2F activity when compared with normal keratinocytes. Indeed, deliberate E2F1 deregulation has been shown to induce hyperplasia and skin tumor formation. In this study, we report on a dual role for E2F as a mediator of keratinocyte proliferation and modulator of squamous differentiation. Overexpression of E2F isoforms in confluent primary keratinocyte cultures resulted in suppression of differentiation-associated markers. Moreover, we found that the DNA binding domain and the trans-activation domain of E2F1 are important in mediating suppression of differentiation. Use of a dominant/negative form of E2F1 ( E2F d/n) found that E2F inhibition alone is sufficient to suppress the activity of proliferation-associated markers but is not capable of inducing differentiation markers. However, if the E2F d/n is expressed in differentiated keratinocytes, differentiation marker activity is further induced, suggesting that E2F may act as a modulator of squamous differentiation. We therefore examined the effects of E2F d/n in a differentiation- insensitive SCC cell line. We found that treatment with the differentiating agent, 12-O-tetradecanoyl- phorbol-13-acetate (TPA), or expression of E2F d/n alone had no effect on differentiation markers. However, a combination of E2F d/n + TPA induced the expression of differentiation markers. Combined, these data indicate that E2F may play a key role in keratinocyte differentiation. These data also illustrate the unique potential of anti-E2F therapies in arresting proliferation and inducing differentiation of SCCs.
Keyword Biochemistry & Molecular Biology
Human Epidermal-keratinocytes
Transcription Factor E2f1
Skin Tumor-development
S-phase Entry
Retinoblastoma Protein
Retinoic Acid
In-vivo
Functional-characterization
Terminal Differentiation
Deregulated Expression
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 01:24:43 EST