Targeted deletion of TGFβ1 in basal keratinocytes causes profound defects in stratified squamous epithelia and aberrant melanocyte migration

Chalmers, Fiona; Dusold, Justyn E; Shaik, Javed A.; Walsh, Hailey A; Glick, Adam B.

doi:10.1016/j.ydbio.2022.02.009

Cited by 3 publications

(2 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 A), is compatible with transcriptional activation through two evolutionary conserved SMAD2/3 binding sites in the ΔNP63 promoter 54 . Although relatively little is known about TAP63 transcriptional regulation 9 , experiments in Tgfb1 -null mice also found that ΔNP63 and TAP63 mRNA were co-regulated 40 , in agreement with our data of similar effects on both isoforms. In addition, we found that the baseline level of TAP63 mRNA but not ΔNP63 mRNA is influenced by SB431542, indicating differences in regulation of the two variants.…”

Section: Discussionsupporting

confidence: 91%

“…On the contrary, TGFβ was reported to decrease 26 , 38 , and inhibition of SMAD activity to increase ΔNp63 38 , 39 . In vivo, Tgfb1 deletion in basal squamous cells caused a dose-dependent reduction of p63 in these cells at birth, with a subsequent increase in suprabasal cells in hemizygous Tgfb1 +/- mice, revealing cell-type and dose- and time-dependent effects of TGFβ on p63 in normal keratinocytes 40 .…”

Section: Introductionmentioning

confidence: 90%

See 1 more Smart Citation

Complex and variable regulation of ΔNp63 and TAp63 by TGFβ has implications for the dynamics of squamous cell epithelial to mesenchymal transition

Pokorná,

Tylichová,

Vojtesek

et al. 2024

Sci Rep

View full text Add to dashboard Cite

TGFβ has roles in inflammation, wound healing, epithelial to mesenchymal transition (EMT), and cancer stem cell states, and acts as a tumor suppressor gene for squamous cell carcinoma (SCC). SCCs are also characterized by high levels of ΔNp63, which induces epithelial cell phenotypes and maintains squamous stem cells. Previous studies indicate a complex interplay between ΔNp63 and TGFβ signaling, with contradictory effects reported. We investigated the effects of TGFβ on p63 isoform proteins and mRNAs in non-malignant squamous and SCC cells, and the role of either canonical or non-canonical TGFβ signaling pathways. TGFβ selectively increased ΔNp63 protein levels in non-malignant keratinocytes in association with SMAD3 activation and was prevented by TGFβ receptor inhibition, indicating activation of canonical TGFβ pathway signaling. TP63 isoform mRNAs showed discordance from protein levels, with an initial increase in both TAP63 and ΔNP63 mRNAs followed by a decrease at later times. These data demonstrate complex and heterogeneous effects of TGFβ in squamous cells that depend on the extent of canonical TGFβ pathway aberrations. The interplay between TGFβ and p63 is likely to influence the magnitude of EMT states in SCC, with clinical implications for tumor progression and response to therapy.

show abstract

Section: Discussionsupporting

confidence: 91%