Universität zu Köln

Kirschberg, Matthias ORCID: 0000-0002-3682-7371, Syed, Adnan Shahzad, Donmez, Hanife Guler, Heuser, Sandra, Wilbrand-Hennes, Astrid, Alonso, Angel, Hufbauer, Martin and Akguel, Baki (2021). Novel Insights Into Cellular Changes in HPV8-E7 Positive Keratinocytes: A Transcriptomic and Proteomic Analysis. Front. Microbiol., 12. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-302X

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Abstract

Human papillomavirus type 8 (HPV8) is associated with the development of non-melanoma skin cancer. In the past we already delved into the mechanisms involved in keratinocyte invasion, showing that the viral E7 oncoprotein is a key player that drives invasion of basal keratinocytes controlled by the extracellular protein fibronectin. To unravel further downstream effects in E7 expressing keratinocytes we now aimed at characterizing gene and protein/phosphoprotein alterations to narrow down on key cellular targets of HPV8-E7. We now show that gene expression of GADD34 and GDF15 are strongly activated in the presence of E7 in primary human keratinocytes. Further analyses of fibronectin-associated factors led to the identification of the Src kinase family members Fyn and Lyn being aberrantly activated in the presence of HPV8-E7. Phospho-proteomics further revealed that E7 not only targets cell polarity and cytoskeletal organization, but also deregulates the phosphorylation status of nuclear proteins involved in DNA damage repair and replication. Many of these differentially phosphorylated proteins turned out to be targets of Fyn and Lyn. Taken together, by using unbiased experimental approaches we have now arrived at a deeper understanding on how fibronectin may affect the signaling cascades in HPV8 positive keratinocytes, which may be key for skin tumorigenesis and that may also aid in the development of novel therapeutic approaches for betaHPV-mediated cancers.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kirschberg, Matthias UNSPECIFIED orcid.org/0000-0002-3682-7371 UNSPECIFIED Syed, Adnan Shahzad UNSPECIFIED UNSPECIFIED UNSPECIFIED Donmez, Hanife Guler UNSPECIFIED UNSPECIFIED UNSPECIFIED Heuser, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Wilbrand-Hennes, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Alonso, Angel UNSPECIFIED UNSPECIFIED UNSPECIFIED Hufbauer, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Akguel, Baki UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-581726
DOI:	10.3389/fmicb.2021.672201
Journal or Publication Title:	Front. Microbiol.
Volume:	12
Date:	2021
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1664-302X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN PAPILLOMAVIRUSES; E7 PROTEIN; DIFFERENTIATION; KINASE; EXPRESSION; GROWTH; E6; INVASION; GENES Multiple languages Microbiology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58172