RESUMEN
High-risk human papillomavirus (HPV) E7 proteins enable oncogenic transformation of HPV-infected cells by inactivating host cellular proteins. High-risk but not low-risk HPV E7 target PTPN14 for proteolytic degradation, suggesting that PTPN14 degradation may be related to their oncogenic activity. HPV infects human keratinocytes but the role of PTPN14 in keratinocytes and the consequences of PTPN14 degradation are unknown. Using an HPV16 E7 variant that can inactivate retinoblastoma tumor suppressor (RB1) but cannot degrade PTPN14, we found that high-risk HPV E7-mediated PTPN14 degradation impairs keratinocyte differentiation. Deletion of PTPN14 from primary human keratinocytes decreased keratinocyte differentiation gene expression. Related to oncogenic transformation, both HPV16 E7-mediated PTPN14 degradation and PTPN14 deletion promoted keratinocyte survival following detachment from a substrate. PTPN14 degradation contributed to high-risk HPV E6/E7-mediated immortalization of primary keratinocytes and HPV+ but not HPV- cancers exhibit a gene-expression signature consistent with PTPN14 inactivation. We find that PTPN14 degradation impairs keratinocyte differentiation and propose that this contributes to high-risk HPV E7-mediated oncogenic activity independent of RB1 inactivation.
Asunto(s)
Diferenciación Celular , Transformación Celular Viral , Papillomavirus Humano 16/metabolismo , Queratinocitos/enzimología , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteolisis , Línea Celular , Supervivencia Celular , Regulación de la Expresión Génica , Papillomavirus Humano 16/genética , Humanos , Queratinocitos/patología , Queratinocitos/virología , Proteínas E7 de Papillomavirus/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Alcohol use disorders are associated with dysfunctional social relationships and stress responses. The neuropeptides oxytocin (OT) and vasopressin (AVP) are known to orchestrate or mediate many aspects of social behavior, stress responses, and ingestive behaviors. Because of the overlap between the effects of alcohol and the roles of OT and AVP, we sought to determine whether alcohol consumption altered expression of OT and AVP in the paraventricular nucleus (PVN) of the hypothalamus, one of the key sites for OT and AVP synthesis. METHODS: Pair-housed adult male prairie voles were allowed to consume 15% ethanol versus water in the home cage continuously (Continuous-Access [CA] group) or every other day for 4 hours (Intermittent-Access [IA] group). Control animals never had access to alcohol. After 7 weeks, animals were sacrificed and their brains were removed and immunohistochemical analysis of OT- and AVP-immunopositive neurons was performed. RESULTS: OT-immunopositive neurons were significantly decreased in the anterior PVN in the CA but not IA group, relative to Control animals, suggesting that continuous alcohol consumption decreases the number of OT neurons. There was no effect of alcohol consumption on posterior PVN OT neurons, and no effect on PVN AVP neurons. CONCLUSIONS: These data show that continuous-access voluntary alcohol consumption is associated with decreased OT neurons in the anterior PVN, suggesting that alcohol-induced alterations in the OT system should be investigated as a mechanism for alcohol-related changes in social behavior, stress responses, and exacerbation of alcohol use disorders.
