Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism

Erica L. Kinney, Satoshi Tanida, Amelie A. Rodrigue, Joanna K. Johnson, Van S. Tompkins, Daitoku Sakamuro

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Adenovirus E1A oncogene transforms primary rodent fibroblasts in cooperation with activated Ras. Conversely, the c-Myc oncoprotein-binding tumor suppressor, Bin1, inhibits Ras/E1A-mediated cell transformation. Since E1A does not directly bind to and inhibit Bin1, the primary mechanism by which E1A counteracts Bin1 to liberate oncogenic c-Myc activity is poorly understood. Here we show that wild-type E1A, but not an Rb binding-defective E1A mutant, suppresses endogenous Bin1 expression in cultured rodent fibroblasts. Similarly, other anti-Rb agents, such as human papillomavirus E7, mitogenic stimuli, and small interfering RNA (siRNA) for Rb, consistently decrease Bin1 promoter activity. In contrast, serum starvation, which activates Rb, enhances endogenous Bin1 levels. These findings suggest that Bin1 may be a novel component of Rb-mediated G1 arrest. Consistent with this premise, chromatin immunoprecipitation assays demonstrate that Rb protein directly interacts with the Bin1 promoter only upon removal of serum. Furthermore, ectopically expressed E2F1, which is primarily inhibited by Rb under serum-starved condition, represses Bin1 promoter activity in a manner that is dependent on the DNA-binding and transactivation domains of E2F1. Lastly, depletion of endogenous Bin1 per se is biologically meaningful since antisense or siRNA of Bin1 transfection releases endogenous c-Myc transcriptional activity and, concomitantly, accelerates cell proliferation. Our results suggest that BinI gene suppression caused by oncogenic E1A via Rb inactivation is an essential step in cell cycle progression promoted by c-Myc, and subsequently, E1A transformation. We propose a novel G1 arrest signaling mechanism by which Rb indirectly curbs oncogenic c-Myc activity via sustaining Bin1 expression.

Original languageEnglish (US)
Pages (from-to)621-631
Number of pages11
JournalJournal of Cellular Physiology
Volume216
Issue number3
DOIs
StatePublished - Sep 1 2008

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Oncogene Proteins
Cell proliferation
Fibroblasts
Adenoviridae
Small Interfering RNA
Cell Proliferation
Curbs
Retinoblastoma Protein
Rodentia
Serum
Chromatin
Tumors
Assays
Genes
Chromatin Immunoprecipitation
Cells
Starvation
Oncogenes
Transcriptional Activation
Transfection

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism. / Kinney, Erica L.; Tanida, Satoshi; Rodrigue, Amelie A.; Johnson, Joanna K.; Tompkins, Van S.; Sakamuro, Daitoku.

In: Journal of Cellular Physiology, Vol. 216, No. 3, 01.09.2008, p. 621-631.

Research output: Contribution to journalArticle

Kinney, Erica L. ; Tanida, Satoshi ; Rodrigue, Amelie A. ; Johnson, Joanna K. ; Tompkins, Van S. ; Sakamuro, Daitoku. / Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism. In: Journal of Cellular Physiology. 2008 ; Vol. 216, No. 3. pp. 621-631.
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AB - Adenovirus E1A oncogene transforms primary rodent fibroblasts in cooperation with activated Ras. Conversely, the c-Myc oncoprotein-binding tumor suppressor, Bin1, inhibits Ras/E1A-mediated cell transformation. Since E1A does not directly bind to and inhibit Bin1, the primary mechanism by which E1A counteracts Bin1 to liberate oncogenic c-Myc activity is poorly understood. Here we show that wild-type E1A, but not an Rb binding-defective E1A mutant, suppresses endogenous Bin1 expression in cultured rodent fibroblasts. Similarly, other anti-Rb agents, such as human papillomavirus E7, mitogenic stimuli, and small interfering RNA (siRNA) for Rb, consistently decrease Bin1 promoter activity. In contrast, serum starvation, which activates Rb, enhances endogenous Bin1 levels. These findings suggest that Bin1 may be a novel component of Rb-mediated G1 arrest. Consistent with this premise, chromatin immunoprecipitation assays demonstrate that Rb protein directly interacts with the Bin1 promoter only upon removal of serum. Furthermore, ectopically expressed E2F1, which is primarily inhibited by Rb under serum-starved condition, represses Bin1 promoter activity in a manner that is dependent on the DNA-binding and transactivation domains of E2F1. Lastly, depletion of endogenous Bin1 per se is biologically meaningful since antisense or siRNA of Bin1 transfection releases endogenous c-Myc transcriptional activity and, concomitantly, accelerates cell proliferation. Our results suggest that BinI gene suppression caused by oncogenic E1A via Rb inactivation is an essential step in cell cycle progression promoted by c-Myc, and subsequently, E1A transformation. We propose a novel G1 arrest signaling mechanism by which Rb indirectly curbs oncogenic c-Myc activity via sustaining Bin1 expression.

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