Human papillomavirus E7 protein deregulates mitosis via an association with nuclear mitotic apparatus protein 1.
We previously observed that high-risk human papillomavirus type 16 (HPV16) E7 expression leads to the delocalization of dynein from mitotic spindles (C. L. Nguyen, M. E. McLaughlin-Drubin, and K. Munger, Cancer Res. 68:8715-8722, 2008). Here, we show that HPV16 E7 associates with nuclear mitotic apparatus protein 1 (NuMA) and that NuMA binding and the ability to induce dynein delocalization map to similar carboxyl-terminal sequences of E7. Additionally, we show that the delocalization of dynein from mitotic spindles by HPV16 E7 and the interaction between HPV16 E7 and NuMA correlate with the induction of defects in chromosome alignment during prometaphase even in cells with normal centrosome numbers. Furthermore, low-risk HPV6b and HPV11 E7s also associate with NuMA and also induce a similar mitotic defect. It is possible that the disruption of mitotic events by HPV E7, via targeting of the NuMA/dynein complex and potentially other NuMA-containing complexes, contributes to viral maintenance and propagation potentially through abrogating the differentiation program of the infected epithelium. Furthermore, in concert with activities specific to high-risk HPV E6 and E7, such as the inactivation of the p53 and pRB tumor suppressors, respectively, the disruption of the NuMA/dynein network may result in mitotic errors that would make an infected cell more prone to the accumulation of aneuploidy even in the absence of supernumerary centrosomes.
Nguyen
Christine L
CL
Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Münger
Karl
K
D034961:Antigens, Nuclear / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002875:Chromosomes / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000472:pathogenicity*; D006801:Humans; D008938:Mitosis; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D049468:Prometaphase / Q000502:physiology; D011485:Protein Binding; D025941:Protein Interaction Mapping
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; C085208:E7 protein, Human papillomavirus 6b; C493190:E7 protein, human papillomavirus 11; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D004398:Dyneins