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FGF8, c-Abl and p300 participate in a pathway that controls stability and function of the ΔNp63α protein.

Restelli M, Molinari E, Marinari B, Conte D, Gnesutta N, Costanzo A, Merlo GR, Guerrini L - Hum. Mol. Genet. (2015)

Bottom Line: Notably, the natural mutant ΔNp63α-K193E, associated to the Split-Hand/Foot Malformation-IV syndrome, cannot be acetylated by this pathway.This mutant ΔNp63α protein displays promoter-specific loss of DNA binding activity and consequent altered expression of development-associated ΔNp63α target genes.Our results link FGF8, c-Abl and p300 in a regulatory pathway that controls ΔNp63α protein stability and transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences, Università degli Studi di Milano, 20133 Milano, Italy.

No MeSH data available.


Related in: MedlinePlus

FGF8 positively regulates ΔNp63α protein stability in mice embryonic limb buds. FGF8, c-Abl and p300 are component of a regulatory pathway that leads to ΔNp63α stabilization and transcriptional activation in embryonic limb buds. Exposure of AER cells to FGF8 induces a signaling intracellular cascade that activates c-Abl causing ΔNp63α phosphorylation on tyrosine residues. This phosphorylation event is indispensable for the interaction of ΔNp63α with the p300 acetyl-transferases; acetylation of ΔNp63α result in its stabilization and transcriptional activation. In the absence of FGF8, or in the presence of p63 mutations, like the SHFM-associated K193E mutation, this signaling pathway is not active leading to improper expression of genes involved in limb development. This pathway could be relevant for correct AER stratification (in the scheme marked in yellow) ensuring correct limb outgrowth.
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DDV151F7: FGF8 positively regulates ΔNp63α protein stability in mice embryonic limb buds. FGF8, c-Abl and p300 are component of a regulatory pathway that leads to ΔNp63α stabilization and transcriptional activation in embryonic limb buds. Exposure of AER cells to FGF8 induces a signaling intracellular cascade that activates c-Abl causing ΔNp63α phosphorylation on tyrosine residues. This phosphorylation event is indispensable for the interaction of ΔNp63α with the p300 acetyl-transferases; acetylation of ΔNp63α result in its stabilization and transcriptional activation. In the absence of FGF8, or in the presence of p63 mutations, like the SHFM-associated K193E mutation, this signaling pathway is not active leading to improper expression of genes involved in limb development. This pathway could be relevant for correct AER stratification (in the scheme marked in yellow) ensuring correct limb outgrowth.

Mentions: Here we report that FGF8, c-Abl, p300 and ΔNp63α are functionally linked in a molecular pathway modulating ΔNp63α activity and stability. Our data show that treatments with FGF8, a signaling molecule essential for limb outgrowth and patterning, result in increased ΔNp63α protein stability, both in cultured cells and in embryonic mouse limb buds ex vivo. Based on these data and previous findings from our team (23), we propose a model in which FGF8 promotes the interaction of c-Abl and ΔNp63α, and that this interaction is required for the consequent association of ΔNp63α with p300, leading to ΔNp63α acetylation (scheme in Fig. 7). When such acetylation is inefficient, due to reduced FGF8 expression or to mutation of the p300 target lysine K193 in ΔNp63α, limb developmental defects ensue.Figure 7.


FGF8, c-Abl and p300 participate in a pathway that controls stability and function of the ΔNp63α protein.

Restelli M, Molinari E, Marinari B, Conte D, Gnesutta N, Costanzo A, Merlo GR, Guerrini L - Hum. Mol. Genet. (2015)

FGF8 positively regulates ΔNp63α protein stability in mice embryonic limb buds. FGF8, c-Abl and p300 are component of a regulatory pathway that leads to ΔNp63α stabilization and transcriptional activation in embryonic limb buds. Exposure of AER cells to FGF8 induces a signaling intracellular cascade that activates c-Abl causing ΔNp63α phosphorylation on tyrosine residues. This phosphorylation event is indispensable for the interaction of ΔNp63α with the p300 acetyl-transferases; acetylation of ΔNp63α result in its stabilization and transcriptional activation. In the absence of FGF8, or in the presence of p63 mutations, like the SHFM-associated K193E mutation, this signaling pathway is not active leading to improper expression of genes involved in limb development. This pathway could be relevant for correct AER stratification (in the scheme marked in yellow) ensuring correct limb outgrowth.
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Related In: Results  -  Collection

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DDV151F7: FGF8 positively regulates ΔNp63α protein stability in mice embryonic limb buds. FGF8, c-Abl and p300 are component of a regulatory pathway that leads to ΔNp63α stabilization and transcriptional activation in embryonic limb buds. Exposure of AER cells to FGF8 induces a signaling intracellular cascade that activates c-Abl causing ΔNp63α phosphorylation on tyrosine residues. This phosphorylation event is indispensable for the interaction of ΔNp63α with the p300 acetyl-transferases; acetylation of ΔNp63α result in its stabilization and transcriptional activation. In the absence of FGF8, or in the presence of p63 mutations, like the SHFM-associated K193E mutation, this signaling pathway is not active leading to improper expression of genes involved in limb development. This pathway could be relevant for correct AER stratification (in the scheme marked in yellow) ensuring correct limb outgrowth.
Mentions: Here we report that FGF8, c-Abl, p300 and ΔNp63α are functionally linked in a molecular pathway modulating ΔNp63α activity and stability. Our data show that treatments with FGF8, a signaling molecule essential for limb outgrowth and patterning, result in increased ΔNp63α protein stability, both in cultured cells and in embryonic mouse limb buds ex vivo. Based on these data and previous findings from our team (23), we propose a model in which FGF8 promotes the interaction of c-Abl and ΔNp63α, and that this interaction is required for the consequent association of ΔNp63α with p300, leading to ΔNp63α acetylation (scheme in Fig. 7). When such acetylation is inefficient, due to reduced FGF8 expression or to mutation of the p300 target lysine K193 in ΔNp63α, limb developmental defects ensue.Figure 7.

Bottom Line: Notably, the natural mutant ΔNp63α-K193E, associated to the Split-Hand/Foot Malformation-IV syndrome, cannot be acetylated by this pathway.This mutant ΔNp63α protein displays promoter-specific loss of DNA binding activity and consequent altered expression of development-associated ΔNp63α target genes.Our results link FGF8, c-Abl and p300 in a regulatory pathway that controls ΔNp63α protein stability and transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences, Università degli Studi di Milano, 20133 Milano, Italy.

No MeSH data available.


Related in: MedlinePlus