title: Overexpression of YAP1 induces immortalization of normal human keratinocytes by blocking clonal evolution.
abstract: YAP1 is a transcriptional co-activator able to bind several transcription factors. YAP1 was termed a candidate oncogene after it was shown to be in human chromosome 11q22 amplicon; besides the genomic amplification, several experiments indicated that it has oncogenic function. However, YAP1 was also reported to be a tumor suppressor as its gene locus is deleted in some breast cancers. To clarify the role of this protein in the physiology of rapidly renewal cells, we investigated YAP1 in human keratinocytes. Here, we show that YAP1 overexpression in primary human keratinocytes blocks clonal evolution and induces cell immortalization, but not malignant transformation. YAP1 overexpression led to an increase in cell proliferation, colony forming efficiency and holoclone percentage. Cells escaped from senescence, immortalized but still remained unable to grow in soft agar or express mesenchymal markers, suggesting that YAP1 overexpression is not sufficient to promote a complete epithelial-mesenchymal transition and tumorigenic transformation. Protein analysis showed an increase in epithelial proliferation markers and a decrease in epithelial differentiation markers. The expression of LEKTI, a late differentiation marker, dramatically dropped to undetectable levels. Taken together, these data suggest that YAP1-overexpressing keratinocytes are maintained in the proliferative compartment.
authors.affiliation: Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: D'Addario
authors.forename: Claudia
authors.initials: C
authors.lastname: Abbruzzese
authors.forename: Marco
authors.initials: M
authors.lastname: Lo Iacono
authors.forename: Massimo
authors.initials: M
authors.lastname: Teson
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Golisano
authors.forename: Virginia
authors.initials: V
authors.lastname: Barone
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000096:biosynthesis; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human