Competitive nuclear export of cyclin D1 and Hic-5 regulates anchorage-dependence of cell growth and survival

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Because the oncogenicity of cyclin D1 depends on its subcellular localization, the regulatory mechanisms have been under intense investigation. Here we discovered that the nuclear localization of cyclin D1 was anchorage-dependent and regulated by a focal adhesion protein, Hic-5, shuttling in and out of the nucleus through the CRM1 export system, which localized cyclin D1 in the nucleus by counteracting the nuclear export of cyclin D1. In non-adherent cells, cyclin D1 was actively exported from the nucleus because the shuttling of Hic-5 was interrupted by an elevated level of reactive oxygen species (ROS). Conversely, shuttling of Hic-5 which acquired insensitivity to ROS allowed nuclear localization of cyclin D1 and a concomitant escape of cells from growth arrest or apoptosis in non-adherent cells. Of interest, activated ras circumvented the above regulation and achieved predominant nuclear localization of cyclin D1 and anchorage-independent growth in non-adherent cells. Together, a new molecular aspect of cyclin D1, the anchorage-dependency of its nuclear localization, has emerged; this deregulation is intimately associated with tumorigenesis, permitting anchorage-independent growth of cells.