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Expression data from BAX/BAK double knockout mouse embryonic fibroblast at baseline and following exposure to genotoxic stress.

ABSTRACT: The BCL-2 family proteins are central regulators of apoptosis. However, cells doubly deficient for BAX and BAK or overexpressing BCL-2 still succumb to oxidative stress upon DNA damage or loss of matrix attachment. Our studies indicate a central role for the transcription factor deltaNp63alpha (referred to as p63 from this point forward) in this form of non-apoptotic cell death. We used microarrays to investigate gene expression in apoptosis-incompetent cells expressing a control vector or p63, at baseline and following exposure to genotoxic stress, to further elucidate molecular mechanisms regulating this type of non-apoptotic death and the role of p63 in this context.

ORGANISM(S): Mus musculus

PROVIDER: GSE106214 | GEO | 2020/10/25

REPOSITORIES: GEO

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Project description:The p53 homologue, p63, is critical for normal epidermal development. While overexpression of deltaNp63alpha has been reported in squamous cell cancers, the contribution of p63 to cancer pathogenesis remains unclear. We previously demonstrated that overexpressed deltaNp63alpha aberrantly maintains proliferation of primary epidermal keratinocytes under conditions that normally induce growth arrest and differentiation. To identify target genes impacted by dysregulated deltaNp63alpha that may contribute to squamous cancer development and progression, microarray analyses were performed. Herein we report that elevated deltaNp63alpha differentially regulates genes in primary mouse keratinocytes involved in a variety of cellular functions, including cell cycle regulation, differentiation, skin barrier formation and function, apoptosis, host defense/inflammation, adhesion, migration and invasion. Of note, multiple protease inhibitor mRNAs were coordinately downregulated under both proliferating and differentiating culture conditions. These downregulated genes include two serine protease inhibitors: maspin (serpinB5) and plasminogen activator inhibitor-2 (PAI-2; serpinB2), as well as a tissue inhibitor of metalloproteinase-3 (TIMP-3). Correspondingly, secreted levels of TIMP-3 and PAI-2 protein declined in the presence of dysregulated deltaNp63alpha, while secreted maspin protein levels remained stable. Intracellular maspin protein expression decreased in response to overexpressed deltaNp63alpha, as did intracellular PAI-2. Unlike PAI-2 and maspin, TIMP-3 protein was not detected intracellularly in control or deltaNp63alpha-overexpressing keratinocytes, supporting a solely extracellular function for TIMP-3. Electrophoretic mobility shift assays using a p53/p63 consensus DNA binding sequence from the maspin promoter revealed binding of an endogenous transcription factor(s) to the consensus sequence in normal keratinocytes that was disrupted by overexpressed deltaNp63alpha. This binding was also interrupted by the addition of a p73 antibody, but not antibodies to p63 or p53, and was absent in samples derived from p73(-/-) keratinocytes, confirming p73 as a constituent of the endogenous transcription factor complex. These data suggest protease inhibitors as novel targets of dysregulated deltaNp63alpha in cancer pathogenesis.

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Expression data from BAX/BAK double knockout mouse embryonic fibroblast at baseline and following exposure to genotoxic stress.

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