Abstract
Cyclin D1 is a proto-oncogene whose amplification and overexpression are frequently associated with human cancers (Diehl, 2002). Because its subcellular localization is of critical importance for its oncogenicity, the regulatory mechanisms have been under intense investigation. Here we discovered that the nuclear localization of cyclin D1 was anchorage-dependent, and its disruption caused anchorage-independent growth and survival of cells, a hallmark of cellular transformation. In adherent cells, cyclin D1 was localized in the nucleus by a focal adhesion protein, Hic-5, shuttling in and out of the nucleus through the CRM1 export system (Shibanuma et al. 2003) and thereby counteracting the nuclear export of cyclin Dl. In non-adherent cells, cyclin Dl was actively exported from the nucleus because the shuttling of Hic-5, which is redox-sensitive (Shibanuma et al. 2003), was interrupted by an elevated level of reactive oxygen species (ROS). However, when a mutant with the shuttling ability resistant to ROS was introduced into cells, cyclin Dl was detained in the nucleus, and importantly, a significant population of cells survived under non-adherent conditions. Of interest, the discovered phenomenon interconnected the oncogenic potential of two oncogenes, as activated ras circumvented the above regulation and achieved the predominant nuclear localization of cyclin Dl and thus, growth in non-adherent cells.
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Mori, K., Oshima, Y., Nose, K., Shibanuma, M. (2009). Competitive Nuclear Export of Cyclin D1 and Hic-5 Regulates Anchorage-Dependence of Cell Growth and Survival. In: Tachikawa, T., Nose, K., Ohmori, T., Adachi, M. (eds) New Trends in the Molecular and Biological Basis for Clinical Oncology. Springer, Tokyo. https://doi.org/10.1007/978-4-431-88663-1_15
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DOI: https://doi.org/10.1007/978-4-431-88663-1_15
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