Nguyen Christine L, McLaughlin-Drubin Margaret E, Münger Karl
Infectious Diseases Division, Channing Laboratories, Brigham and Women's Hospital and Committee on Virology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cancer Res. 2008 Nov 1;68(21):8715-22. doi: 10.1158/0008-5472.CAN-08-1303.
Dynein is a minus end-directed microtubule motor that transports numerous cargoes throughout the cell. During mitosis, dynein motor activity is necessary for the positioning of spindle microtubules and has also been implicated in inactivating the spindle assembly checkpoint. Mutations in dynein motor and/or accessory proteins are associated with human disease, including cancer, and the delocalization of dynein from mitotic spindles has been correlated with an increased incidence of multipolar spindle formation in some cancer cells that contain supernumerary centrosomes. The high-risk human papillomavirus type 16 (HPV16) E7 oncoprotein induces centrosome overduplication and has been shown to cause multipolar mitotic spindle formation, a diagnostic hallmark of HPV-associated neoplasias. Here, we show that HPV16 E7 expression leads to an increased population of mitotic cells with dynein delocalized from the mitotic spindle. This function maps to sequences of HPV16 E7 that are distinct from the region necessary for centrosome overduplication. However, contrary to previous reports, we provide evidence that dynein delocalization by HPV16 E7 is neither necessary nor sufficient to cause the formation of multipolar mitoses.
动力蛋白是一种向微管负端移动的分子马达，可在整个细胞内运输多种货物。在有丝分裂期间，动力蛋白的马达活性对于纺锤体微管的定位是必需的，并且也与纺锤体组装检查点的失活有关。动力蛋白马达和/或辅助蛋白的突变与人类疾病相关，包括癌症，并且在一些含有多余中心体的癌细胞中，动力蛋白从有丝分裂纺锤体上的错位与多极纺锤体形成的发生率增加相关。高危型人乳头瘤病毒16型（HPV16）E7癌蛋白可诱导中心体过度复制，并且已被证明可导致多极有丝分裂纺锤体形成，这是HPV相关肿瘤形成的诊断标志。在这里，我们表明HPV16 E7的表达导致有丝分裂细胞群体增加，其中动力蛋白从有丝分裂纺锤体上错位。该功能定位于HPV16 E7的序列，该序列与中心体过度复制所需的区域不同。然而，与先前的报道相反，我们提供的证据表明，HPV16 E7引起的动力蛋白错位既不是导致多极有丝分裂形成的必要条件也不是充分条件。
