The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle

The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle

^*Department of Pathology and Harvard Center for Cancer Biology, ^†Department of Pathology, Solid Tumor Cytogenetics, Brigham and Women's Hospital, and ^‡Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved June 27, 2000 (received for review March 3, 2000)

Abstract

Loss of genomic integrity is a defining feature of many human malignancies, including human papillomavirus (HPV)-associated preinvasive and invasive genital squamous lesions. Here we show that aberrant mitotic spindle pole formation caused by abnormal centrosome numbers represents an important mechanism in accounting for numeric chromosomal alterations in HPV-associated carcinogenesis. Similar to what we found in histopathological specimens, HPV-16 E6 and E7 oncoproteins cooperate to induce abnormal centrosome numbers, aberrant mitotic spindle pole formation, and genomic instability. The low-risk HPV-6 E6 and E7 proteins did not induce such abnormalities. Whereas the HPV-16 E6 oncoprotein has no immediate effects on centrosome numbers, HPV-16 E7 rapidly induces abnormal centrosome duplication. Thus our results suggest a model whereby HPV-16 E7 induces centrosome-related mitotic disturbances that are potentiated by HPV-16 E6.

Footnotes

↵ § To whom reprint requests should be addressed at: Department of Pathology and Harvard Center for Cancer Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5701. E-mail: karl_munger{at}hms.harvard.edu.
This paper was submitted directly (Track II) to the PNAS office.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.170093297.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.170093297
Abbreviations:

HPV,

human papillomavirus;

cdk2,

cyclin-dependent kinase 2;

NHKs,

normal human keratinocytes;

GFP,

green fluorescent protein;

dn,

dominant-negative