u-0126 and Papillomavirus-Infections

Topics: Butadienes; Case-Control Studies; Enzyme Inhibitors; Female; Human papillomavirus 16; Humans; Mitogen-Activated Protein Kinase 12; Neoplasm Proteins; Nitriles; Papillomavirus Infections; RNA Interference; Signal Transduction; Uterine Cervical Neoplasms

Human papillomaviruses (HPVs) are a causative factor in over 90% of cervical and 25% of head and neck squamous cell carcinomas (HNSCCs). The C terminus of the high-risk HPV 16 E6 oncoprotein physically associates with and degrades a non-receptor protein tyrosine phosphatase (PTPN13), and PTPN13 loss synergizes with H-Ras(V12) or ErbB2 for invasive growth in vivo. Oral keratinocytes that have lost PTPN13 and express H-Ras(V12) or ErbB2 show enhanced Ras/RAF/MEK/Erk signaling. In co-transfection studies, wild-type PTPN13 inhibited Ras/RAF/MEK/Erk signaling in HEK 293 cells that overexpress ErbB2, EGFR or H-Ras(V12), whereas an enzymatically inactive PTPN13 did not. Twenty percent of HPV-negative HNSCCs had PTPN13 phosphatase mutations that did not inhibit Ras/RAF/MEK/Erk signaling. Inhibition of Ras/RAF/MEK/Erk signaling using MEK inhibitor U0126 blocked anchorage-independent growth in cells lacking PTPN13. These findings show that PTPN13 phosphatase activity has a physiologically significant role in regulating MAP kinase signaling.

Topics: Animals; Butadienes; Carcinoma, Squamous Cell; Cell Growth Processes; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; Human papillomavirus 16; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Nitriles; Oncogene Proteins, Viral; Papillomavirus Infections; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 13; Receptor, ErbB-2; Repressor Proteins