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Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism.
J Cell Physiol. 2008 Sep; 216(3):621-31.JC

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 Bin1 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.

Authors+Show Affiliations

Division of Cancer Biology, Department of Pathology, School of Medicine and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

18348166

Citation

Kinney, Erica L., et al. "Adenovirus E1A Oncoprotein Liberates c-Myc Activity to Promote Cell Proliferation Through Abating Bin1 Expression Via an Rb/E2F1-dependent Mechanism." Journal of Cellular Physiology, vol. 216, no. 3, 2008, pp. 621-31.
Kinney EL, Tanida S, Rodrigue AA, et al. Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism. J Cell Physiol. 2008;216(3):621-31.
Kinney, E. L., Tanida, S., Rodrigue, A. A., Johnson, J. K., Tompkins, V. S., & Sakamuro, D. (2008). Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism. Journal of Cellular Physiology, 216(3), 621-31. https://doi.org/10.1002/jcp.21437
Kinney EL, et al. Adenovirus E1A Oncoprotein Liberates c-Myc Activity to Promote Cell Proliferation Through Abating Bin1 Expression Via an Rb/E2F1-dependent Mechanism. J Cell Physiol. 2008;216(3):621-31. PubMed PMID: 18348166.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism. AU - Kinney,Erica L, AU - Tanida,Satoshi, AU - Rodrigue,Amelie A, AU - Johnson,Joanna K, AU - Tompkins,Van S, AU - Sakamuro,Daitoku, PY - 2008/3/19/pubmed PY - 2008/8/30/medline PY - 2008/3/19/entrez SP - 621 EP - 31 JF - Journal of cellular physiology JO - J Cell Physiol VL - 216 IS - 3 N2 - 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 Bin1 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. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/18348166/Adenovirus_E1A_oncoprotein_liberates_c_Myc_activity_to_promote_cell_proliferation_through_abating_Bin1_expression_via_an_Rb/E2F1_dependent_mechanism_ L2 - https://doi.org/10.1002/jcp.21437 DB - PRIME DP - Unbound Medicine ER -