engleski

MAML1-induced HPV E6 oncoprotein stability is required for cellular proliferation and migration of cervical tumor-derived cells

To date, more than 200 different Human Papillomavirus (HPV) types have been identified, with differences in tissue tropism and ability to promote malignant transformation of epithelial cells at different anatomical sites. Alpha (α) HPV types infect mucosal tissue, while beta (β) HPV types infect cutaneous epithelial tissue. High- risk (HR) α-HPVs are associated with numerous human malignancies, of which cervical cancer is the most prevalent, while β-HPVs predominantly act as co-factors in skin carcinogenesis. Both α- and β-E6 oncoproteins in their structure have presence of the LXXLL binding motif, which α-E6s utilize to form a complex with E6AP while β-E6s via same binding motif interact with MAML1. Hence, cellular proteins MAML1 and E6AP, share a common LXXLL binding domain, through which this protein-protein interaction occurs. Unlike the well-described E6 oncoprotein stabilization by E6AP, no detailed research has been done on the potential effects on the stability and function of E6 binding to MAML1. Our research shows that LXXLL motif-dependent interaction of HR α-HPVs with MAML1 has a stabilizing effect on E6s’ protein levels. Moreover, a well-defined interaction of β-HPVs with MAML1 serves to increase E6 protein stability. Ablation of both E6AP and MAML1 leads to an even more profound down-regulation of α-E6 protein expression, whereas this is not observed with β-E6. Our results imply the existence of one cellular pool for most of β- E6 that interacts solely with MAML1, whereas there are two cellular pools of HR α-E6, one forming a complex with MAML1 and the other interacting with E6AP. Furthermore, MAML1 induces changes of the HPV-8 E6 cellular localization from the nucleus to the cytosolic fraction, while MAML1 interaction with HR E6 induces a drastic increase of the E6 protein levels in nuclear and membrane cellular compartment. Interestingly, the HR α-E6 /MAML1 complex and the increased stability of E6 does not influence an increase in E6-mediated degradation effect for some of its’ most common cellular targets such as p53 and DLG1. However, MAML1 and E6AP joint co-expression with HR α-E6 leads to a significant increase in cellular proliferation, whereas silencing MAML1 decreases wound healing in HeLa cells. These results demonstrate that HR α-E6 interaction with MAML1 results in E6's increased protein stability, which modulates MAML1's normal cellular activities, that was observed with an increased proliferative capacity of HPV- transformed cancer cells.

cervical cancer ; E6 ; E6AP ; HPV ; MAML1 ; proliferation ; skin cancer

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