Ueda Akihiro, Yoneda-Kato Noriko, Yamanaka Yuji, Nakamae Ikuko, Kato Jun-ya, Cytoplasmic Retention of CDC6 Induces Premature Senescence in Immortalized Cells and Suppresses Tumor Formation in Mice, Journal of Hematology and Oncology Research, Volume 2, Issue 2, 2016, Pages 27-42, ISSN 2372-6601, https://doi.org/10.14302/issn.2372-6601.jhor-16-1125.
(https://oap-researcharticles.org/jhor/article/295)
Abstract: 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.
Keywords: cell cycle; senescence; CDC6; cytoplasmic retention; tumor suppression