Human papillomaviruses (HPV) constitute a large family of viruses that can be subdivided into mucosal and cutaneous types. Mucosal high-risk HPVs are the aetiological agents of cervical cancer. Certain cutaneous HPVs, also referred as to beta types, were first isolated from patients suffering from a rare autosomal recessive cancer-prone genetic disorder, epidermodysplasia verruciformis (EV), and are consistently detected in non-melanoma skin cancer from EV, immunocompromised and normal individuals. However, a direct role of the beta HPV types in cancer development remains to be proven and the transforming properties of the majority of the cutaneous HPVs have been poorly investigated. One of the best characterized beta HPVs is type 38 which displays transforming properties that can be ascribed to E6 and E7 proteins. Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild type p53. This selectively activates transcription of ?Np73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. Recently, we have observed that IFN-? inhibits cell proliferation and affects cell cycle in keratinocytes transformed by both mucosal HR-HPV and cutaneous HPVs. In particular, upon long IFN-? treatments, cutaneous HPV38 transformed cells accumulate in G1 phase and undergo senescence. IFN-? appears to induce this senescence process by upregulating the expression of the tumor suppressor PML. Indeed, experiments of gene silencing via specific siRNAs have shown that PML is essential in the execution of senescence program and p53 and p21 pathways appear to be involved. Preliminary results indicate that p53 co-localyzes with IFN-?-induced PML into Nuclear Bodies and that IFN-? affects p53 phosphorylation status targeting p53 transactivating activity of genes involved in cell proliferation control.
Interferon-beta affects p53 transactivating activity in cutaneous human papillomavirus 38 (HPV38)-transformed keratinocytes
Fiorucci G;
2010
Abstract
Human papillomaviruses (HPV) constitute a large family of viruses that can be subdivided into mucosal and cutaneous types. Mucosal high-risk HPVs are the aetiological agents of cervical cancer. Certain cutaneous HPVs, also referred as to beta types, were first isolated from patients suffering from a rare autosomal recessive cancer-prone genetic disorder, epidermodysplasia verruciformis (EV), and are consistently detected in non-melanoma skin cancer from EV, immunocompromised and normal individuals. However, a direct role of the beta HPV types in cancer development remains to be proven and the transforming properties of the majority of the cutaneous HPVs have been poorly investigated. One of the best characterized beta HPVs is type 38 which displays transforming properties that can be ascribed to E6 and E7 proteins. Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild type p53. This selectively activates transcription of ?Np73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. Recently, we have observed that IFN-? inhibits cell proliferation and affects cell cycle in keratinocytes transformed by both mucosal HR-HPV and cutaneous HPVs. In particular, upon long IFN-? treatments, cutaneous HPV38 transformed cells accumulate in G1 phase and undergo senescence. IFN-? appears to induce this senescence process by upregulating the expression of the tumor suppressor PML. Indeed, experiments of gene silencing via specific siRNAs have shown that PML is essential in the execution of senescence program and p53 and p21 pathways appear to be involved. Preliminary results indicate that p53 co-localyzes with IFN-?-induced PML into Nuclear Bodies and that IFN-? affects p53 phosphorylation status targeting p53 transactivating activity of genes involved in cell proliferation control.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
