Inhibition of TGF-β and NOTCH Signaling by Cutaneous Papillomaviruses

Abstract

Infections with cutaneous papillomaviruses have been linked to cutaneous squamous cell carcinomas that arise in patients who suffer from a rare genetic disorder, epidermodysplasia verruciformis, or those who have experienced long-term, systemic immunosuppression following organ transplantation. The E6 proteins of the prototypical cutaneous human papillomavirus (HPV) 5 and HPV8 inhibit TGF-β and NOTCH signaling. The Mus musculus papillomavirus 1, MmuPV1, infects laboratory mouse strains and causes cutaneous skin warts that can progress to squamous cell carcinomas. MmuPV1 E6 shares biological and biochemical activities with HPV8 E6 including the ability to inhibit TGF-β and NOTCH signaling by binding the SMAD2/SMAD3 and MAML1 transcription factors, respectively. Inhibition of TGF-β and NOTCH signaling is linked to delayed differentiation and sustained proliferation of differentiating keratinocytes. Furthermore, the ability of MmuPV1 E6 to bind MAML1 is necessary for wart and cancer formation in experimentally infected mice. Hence, experimental MmuPV1 infection in mice will be a robust and valuable experimental system to dissect key aspects of cutaneous HPV infection, pathogenesis, and carcinogenesis.

More than just oncogenes: mechanisms of tumorigenesis by human viruses

“…More recently a papillomavirus that infects mice, MmuPV1, has been discovered and is actively being developed as a model of HPV infection [17–19]. MmuPV1 is phylogenetically most related to the cutaneous β- and γ-HPVs and its oncogenic E6 and E7 proteins have biological and biochemical activities that resemble those of β- and γ-HPVs [20–22]. Experimental MmPV1 infections cause cutaneous papillomas that, similar to β-HPV induced lesions, can progress to cutaneous squamous cell carcinomas upon UV exposure [23].…”

“…The TGFβ and NOTCH signaling pathways, which are repressed by β-HPVs, are tumor suppressive at early stages of epithelial carcinogenesis, but are oncogenic at later stages of malignant progression. Hence the observed loss of β-HPVs in cutaneous squamous cell carcinomas may reflect the necessity for reactivation of TGFβ and NOTCH signaling during cancer progression [22]. While α-HPV oncogene expression is generally maintained in the cancers, α-HPVs may contribute to tumorigenesis via a hit-and-run mechanism in Fanconi Anemia patients.…”

Epidermodysplasia Verruciformis: Functional Role of E6 and E7 Oncoproteins as the Link between Viral Infection to Carcinogenesis

“…38,42 This causes their degradation which inhibit the ATM and the ATR, driving carcinogenesis. 43 E6 was found to counteract the downregulation of tumor promoting ∆Np63α and the upregulation of tumor suppressor and miR-203. PMA can induce the C/EBPα transcription factor which is very potent in inducing the differentiation of the keratinocytes which is also an important function in response to the UV induced carcinogenesis.…”

“…44 It gets activated by a cell to cell contact process where the ligands that are anchored to the membrane and belong to the Jagged or the Delta family, bind to the Notch receptors. 43 It is involved in the embryogenesis and in the developmental process of organism. The Notch extracellular truncation fragment is recognized by the gamma secretase complex which lead to the proteolytic process.…”

“…The ICN/RBPJ/MAML complex represents the core NOTCH transcriptional activator complex and then the MAML conscripts' additional co-activators. 43 The NOTCH pathway is observed to be an important factor for the keratinocytes' differentiation and its defect has been involved in the cutaneous SCCs. Studies have shown that the E6 gene is able to interact with MAML1 and intracellular cleaved NOTCH1 (ICN1), inhibiting the NOTCH.…”