Cytoplasmic Retention of CDC6 Induces Premature Senescence in Immortalized Cells and Suppresses Tumor Formation in Mice - Cytoplasmic Retention of CDC6 Induces Premature Senescence in Immortalized Cells and Suppresses Tumor Formation in Mice - Open Access Pub

Senescence is a powerful mechanism that prevents the development of tumors in vivo; however, once tumors are formed, most are refractory to senescence in response to oncogenic stress. Therefore, a novel pathway leading to senescence is required. We herein demonstrated that the cell cycle regulator CDC6 translocated from the nucleus to the cytoplasm during senescence in a leptomycin B-resistant manner. In order to evaluate the translocation of CDC6, we utilized an estrogen receptor (ER) tag to retain CDC6 in the cytoplasm. ER-tagged CDC6 was exclusively cytoplasmic, inhibited cell proliferation, and induced senescence-associated (SA) b-galactosidase activity. Furthermore, ER-CDC6 inhibited the transformation of mouse fibroblasts by the active ras oncogene in vitro, and suppressed tumor formation in NOD-SCID mice. Thus, CDC6 may play a critical role in the regulation of senescence in the cytoplasm in order to counteract tumorigenesis. DOI10.14302/issn.2372-6601.jhor-16-1125 Mammalian cells are equipped with mechanisms that prevent the formation and development of tumors, such as checkpoint controls, DNA damage responses, differentiation, apoptosis, and senescence. Of these, senescence has been proposed to strongly suppress the formation and development of tumors1,2; however, its mechanism of action and pathways have not yet been elucidated in detail. Senescence is characterized by eternal withdrawal from the cell cycle and was originally identified as a mechanism determining the life span of primary cells cultured in vitro; however, subsequent studies reported that it was induced under several different conditions, such as telomere shortening, DNA damage, oxidative stress, the abrupt activation of oncogenes, and the developmental program3, 4, 5. These findings demonstrated that senescence is a cellular response to stress that disables the proliferation of cells. Senescence has been recognized as a part of the system that prevents the tumorigenic transformation of mammalian cells1, 2 by inhibiting cell proliferation, and eliminates damaged cells via an inflammatory process by affecting surrounding cells through secreted factors6. The tumor suppressor, p53, was previously shown to play an important role in senescence and tumor suppression by triggering the expression of a series of genes involved in cell cycle arrest and the onset of senescence, such as the CDK inhibitor p21, which negatively regulates G1 cyclin-CDK complexes, ultimately leading to the dephosphorylation and activation of the Rb protein3. In the initial stage of tumorigenic transformation in