Doi Natsumi, Kunimatsu Yuuki, Fujiura Kouhei, Togari Hiro, Minagi Kenji, Nakaoji Koichi, Hamada Kazuhiko, Temme Achim, Tatsuka Masaaki
Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
Research & Development Division, Pias Corporation, Kobe, Japan.
J Cell Physiol. 2019 Sep;234(9):15134-15146. doi: 10.1002/jcp.28154. Epub 2019 Jan 16.
The molecular signals that regulate mitotic spindle orientation to determine the proper division axis play a critical role in the development and maintenance of tissue homeostasis. However, deregulation of signaling events can result in spindle misorientation, which in turn can trigger developmental defects and cancer progression. Little is known about the cellular signaling pathway involved in the misorientation of proliferating cells that evade apoptosis after DNA damage. In this study, we found that perturbations to spindle orientation were induced in ultraviolet C (UVC)-irradiated surviving cells. N-terminal truncated Rho GDP-dissociation inhibitor β (RhoGDIβ), which is produced by UVC irradiation, distorted the spindle orientation of HeLa cells cultured on Matrigel. The short hairpin RNA-mediated knockdown of RhoGDIβ significantly attenuated UVC-induced misorientation. Subsequent expression of wild-type RhoGDIβ, but not a noncleavable mutant, RhoGDIβ (D19A), again led to a relative increase in spindle misorientation in response to UVC. Our findings revealed that RhoGDIβ impacts spindle orientation in response to DNA damage.
调节有丝分裂纺锤体方向以确定正确分裂轴的分子信号在组织稳态的发育和维持中起着关键作用。然而,信号事件失调会导致纺锤体方向错误,进而引发发育缺陷和癌症进展。对于DNA损伤后逃避凋亡的增殖细胞方向错误所涉及的细胞信号通路知之甚少。在本研究中,我们发现紫外线C(UVC)照射后的存活细胞中纺锤体方向受到了干扰。UVC照射产生的N端截短的Rho GDP解离抑制剂β(RhoGDIβ)使在基质胶上培养的HeLa细胞的纺锤体方向发生扭曲。短发夹RNA介导的RhoGDIβ敲低显著减弱了UVC诱导的方向错误。随后野生型RhoGDIβ的表达,但不是不可切割的突变体RhoGDIβ(D19A),再次导致了对UVC反应中纺锤体方向错误的相对增加。我们的研究结果表明,RhoGDIβ在DNA损伤反应中影响纺锤体方向。