The serine protease inhibitors TLCK and TPCK react with the RB-binding core of HPV-18 E7 protein and abolish its RB-binding capability

Virology
H StöpplerR Schlegel

Abstract

The human papillomaviruses associated with cervical cancer (e.g., HPV-16 and HPV-18) express an E7 oncoprotein which mediates the immortalization of primary genital keratinocytes and the transformation of rodent cells. The 105-amino-acid HPV-18 E7 protein contains two zinc fingers as well as a conserved amino-terminal motif (Rb-binding core) which binds and alters the interactions of the retinoblastoma susceptibility gene product (Rb). We report here that two serine protease inhibitors, tosyl-L-lysine chloromethyl ketone (TLCK) and tosyl-L-phenylalanine chloromethyl ketone (TPCK), reacted with and generated an altered form of the HPV-18 E7 protein. Chemical modification of the E7 protein was initially observed during its extraction and immunoprecipitation from mammalian cells but could also be detected using E7 protein expressed in vitro by reticulocyte lysates. More importantly, TLCK and TPCK were able to modify E7 protein in live keratinocytes following their addition to the culture medium. Site-specific mutagenesis demonstrated that the E7 Rb-binding core (Leu-X-Cys-X-Glu) contained a cysteine residue which was essential for this modification and that the TLCK/TPCK-dependent alteration of the E7 protein abolished its ability...Continue Reading

Citations

Jul 28, 2010·AIDS Research and Therapy·Yong-Jiu JinSteven J Burakoff
Jan 5, 2002·The Journal of Investigative Dermatology. Symposium Proceedings·T YamashitaK Fujinaga
Jun 5, 2013·Virology·Ann Roman, Karl Munger
Mar 28, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·David A DrubinCraig Meyers

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