Data di Pubblicazione:
2013
Citazione:
HACAT AS A MODEL FOR KERATINOCYTESTRANSFORMATION / E. Martynova ; scientific tutor: R. Mantovani. DIPARTIMENTO DI BIOSCIENZE, 2013 May 31. 25. ciclo, Anno Accademico 2012. [10.13130/martynova-elena_phd2013-05-31].
Abstract:
Mutations of the tumor suppressor gene p53 occur in more than 50% of
human malignancies and lead to the loss of suppressor activity. Moreover
frequently p53 mutants gain novel, oncogenic properties by transcriptional
activation of the genes, involved in cellular proliferation, cell survival and
angiogenesis. Today’s challenge is to understand mechanisms underlying the
gain-of-function of mutant p53 proteins.
By the example of KLF4 promoter we demonstrate that mutant p53 can
carries out its gain-of-function by interaction with another p53 family member,
transcription factor p63. In the first report we provide strong evidence that KLF4
is negatively controlled by p63 in normal skin in the presence of physiological
levels of wild type p53 (wtp53) and that this regulation is subverted by
oncogenic mutations of p53, establishing a direct link between these TFs,
commonly overexpressed in squamous cell carcinoma (SCC).
These results inspired us to investigate the mechanisms of mutant p53
gain-of-function on the genome scale. In the second manuscript we demonstrate
that mutant p53 HaCaT alleles are pro-growth and mutp53 have thousands of
binding sites in the human genome; they affect gene expression profoundly,
both by binding with p63 to consensus elements and by being tethered by other
TFs to their locations.
Although 2 mutant p53 alleles are definitely gain-of-function in the
HaCaT, they are not sufficient to render these cells malignant. Based on the
sphere-forming assay we developed novel model for the tumorigenic conversion
of the HaCaT cells: while immortalized keratinocytes display transformed
phenotype in vitro and not tumorigenic upon injection into nude mice, HaCaTderived
spheres give rise to the SCC in vivo. Thus, this simple model can be
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useful for the future studies of the genetic and phenotypic signatures during
SCC initiation and development.
There is an indication that mutant p53 can execute its gain-of-function
via interaction with NF-Y transcription factor. Ongoing study is devoted to the
investigation of NF-YA subunit role in the processes of cellular proliferation
and apoptosis in the cells with different p53 status.
Tipologia IRIS:
Tesi di dottorato
Elenco autori:
E. Martynova
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