ΔNp63α Expression Is Regulated by the Phosphoinositide 3-Kinase Pathway

Abstract

p63 is a homologue of p53 that functions to maintain progenitor cell populations in stratified epithelia. ⌬Np63␣ is overexpressed in epithelial cancers and has been shown to have oncogenic properties. We have previously reported that inhibition of epidermal growth factor receptor signaling results in a decrease in ⌬Np63␣ expression. Here, we demonstrate ⌬Np63␣ is a target of the phosphoinositide-3-kinase (PI3K) pathway downstream of the epidermal growth factor receptor. Treatment of keratinocytes with epidermal growth factor results in an increase in ⌬Np63␣ expression at the mRNA level, which is abrogated by inhibition of PI3K but not mitogen-activated protein kinase signaling. Small interfering RNA-mediated knockdown of the p110␤ catalytic subunit of PI3K results in a decrease in ⌬Np63␣ protein levels in keratinocytes. The results presented herein suggest that regulation of ⌬Np63␣ expression by the PI3K pathway plays a critical role in the survival and proliferative capacity of squamous epithelia.

Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63

“…In addition, consistent with prior reports (41), ΔNp63α protein levels were not significantly affected by E6 and E7 viral oncoproteins when compared with levels in normal keratinocytes ( Figure 1C). Following treatment with LY294002, both normal and E6/E7 keratinocytes exhibited levels of ΔNp63α protein that were 20-30% of diluent-treated control cells, similar to results previously reported (40). In both normal and E6/E7 cells, the reduction in ΔNp63α persisted following UVR.…”

“…As shown in Figure 1A, relative to NHKs, E6/E7 keratinocytes had almost undetectable p53 protein levels, though we have also shown previously that XPC levels are not reduced in E6/E7 (8). Since ΔNp63α, the most abundant p63 isoform in epidermal keratinocytes, appears to be reduced by phosphoinositide 3 kinase (PI3 kinase) inhibition (40), reducing ΔNp63α with the PI3 kinase inhibitor, LY294002, was explored initially in the E6/E7 keratinocyte model. As previously reported (40), LY294002 reduced ΔNp63α mRNA levels in E6/E7 keratinocytes to levels that were only 10% of those observed in control cells ( Figure 1B).…”

“…Since ΔNp63α, the most abundant p63 isoform in epidermal keratinocytes, appears to be reduced by phosphoinositide 3 kinase (PI3 kinase) inhibition (40), reducing ΔNp63α with the PI3 kinase inhibitor, LY294002, was explored initially in the E6/E7 keratinocyte model. As previously reported (40), LY294002 reduced ΔNp63α mRNA levels in E6/E7 keratinocytes to levels that were only 10% of those observed in control cells ( Figure 1B). In addition, consistent with prior reports (41), ΔNp63α protein levels were not significantly affected by E6 and E7 viral oncoproteins when compared with levels in normal keratinocytes ( Figure 1C).…”

p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm

“…Human foreskin epidermal keratinocytes (HEKs) and the human large cell lung carcinoma cells (H1299) were cultured as described previously (Barbieri et al, 2003). HMECs were isolated and cultured as reported previously (Hearnes et al, 2005).…”

The role of p53 protein family in gastrointestinal malignancies

“…20 Recently, DNp63 has been identified as a downstream target of the phosphoinositide 3-kinase (PI3 K) pathway, a cell survival and proliferation pathway in cancer. 21 At least two mechanisms may contribute to the oncogenic properties of the TP63 gene. Overexpression of DNp63 may have an inhibitory effect on p53, p73 or p63.…”