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J Biol Chem, Vol. 275, Issue 20, 14824-14830, May 19, 2000
From the The high risk human papillomaviruses (HPVs) are
associated with carcinomas of cervix and other genital tumors. Previous
studies have identified two viral oncoproteins E6 and E7, which are
expressed in the majority of HPV-associated carcinomas. The ability of
high risk HPV E6 protein to immortalize human mammary epithelial cells has provided a single gene model to study the mechanisms of E6-induced oncogenic transformation. In recent years, it has become clear that in
addition to E6-induced degradation of p53 tumor suppressor protein,
other targets of E6 are required for mammary epithelial cells
immortalization. Using the yeast two-hybrid system, we have identified
a novel interaction of HPV16 E6 with protein kinase PKN, a fatty acid-
and Rho small G protein-activated serine/threonine kinase with a
catalytic domain highly homologous to protein kinase C. We demonstrate
direct binding of high risk HPV E6 proteins to PKN in wheat-germ lysate
in vitro and in 293T cells in vivo. Importantly, E6 proteins of high risk HPVs but not low risk HPVs were
able to bind PKN. Furthermore, all the immortalization-competent and
many immortalization-non-competent E6 mutants bind PKN. These data
suggest that binding to PKN may be required but not sufficient for
immortalizing normal mammary epithelial cells. Finally, we show that
PKN phosphorylates E6, demonstrating for the first time that HPV E6 is
a phosphoprotein. Our finding suggests a novel link between HPV E6
mediated oncogenesis and regulation of a well known phosphorylation cascade.
PKN Binds and Phosphorylates Human Papillomavirus E6
Oncoprotein*
,,,,, and¶
Department of Radiation Oncology, New
England Medical Center and ¶ Department of Biochemistry, Tufts
University School of Medicine, Boston, Massachusetts 02111 and the
§ Graduate School of Science and Technology and Department
of Biology, Faculty of Science, Kobe University,
Kobe 657-8501, Japan
*
This work was supported by National Institutes of Health
Grants CA64823 and CA70195 (to V. B.)The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Box 824, Dept. of
Radiation Oncology, New England Medical Center, 750 Washington St.,
Boston, MA 02111. Tel.: 617-636-4776; Fax: 617-636-6205; E-mail:
vband@olifespan.org.
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