p63 is upstream of IKKα in epidermal development

Candi, Eleonora; Terrinoni, Alessandro; Rufini, Alessandro; Chikh, Anissa; Lena, Anna Maria; Suzuki, Yasuhiro; Sayan, Berna S.; Knight, Richard; Melino, Gerry

doi:10.1242/jcs.03265

Cited by 107 publications

(104 citation statements)

References 29 publications

(40 reference statements)

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“…Further studies are needed to determine if PTPN14 and ING1 are direct transcriptional targets of p63. The functional REs in other target genes recently reported as uniquely regulated by p63 and not p53, such as Shh (Caserta et al, 2006), IKKa (Candi et al, 2006) and PKCg (Ponassi et al, 2006), further support our description of the p63 consensus DNA-binding site and its functional impact on target selectivity in the p53 family.…”

Section: Discussionsupporting

confidence: 87%

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

et al. 2007

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p53 and p63 belong to a family of sequence-specific transcription factors regulating key cellular processes. Differential composition of the p53 and p63 DNA-binding sites may contribute to distinct functions of these protein homologues. We used SELEX (systematic evolution of ligands by exponential enrichment) methodology to identify nucleic acid ligands for p63. We found that p63 bound preferentially to DNA fragments conforming to the 20 bp sequence 5 0 -RRRC(A/G)(A/T)GYYYRRRC(A/T) (C/T)GYYY-3 0 . Relative to the p53 consensus, the p63 consensus DNA-binding site (DBS) was more degenerate, particularly at positions 10 and 11, and was enriched for A/G at position 5 and C/T at position 16 of the consensus. The differences in DNA-binding site preferences between p63 and p53 influenced their ability to activate transcription from select response elements (REs) in cells. A computer algorithm, p63MH, was developed to find candidate p63-binding motifs on input sequences. We identified genes responsive to p63 regulation that contain functional p63 REs. Our results suggest that the sequence composition of REs could be one contributing factor to target gene discrimination between p63 and p53.

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Section: Discussionsupporting

confidence: 87%

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

et al. 2007

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“…3E). A recent study, using in vitro experiments, suggested that induction of IKK␣ by ⌬Np63␣ occurs through an indirect mechanism in Saos2 cells (30). However, our in vivo analyses clearly demonstrate that, when commitment to terminal differentiation occurs, ⌬Np63␣ induces Ikk␣ expression by directly interacting with the Ikk␣ promoter.…”

Section: Resultscontrasting

confidence: 45%

p63 induces key target genes required for epidermal morphogenesis

Koster¹,

Dai

Marinari

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

209

250

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Mice lacking p63, a single gene that encodes a group of transcription factors that either contain (TA) or lack (⌬N) a transactivation domain, fail to develop stratified epithelia as well as epithelial appendages and limbs. ⌬Np63 isoforms are predominantly expressed during late embryonic and postnatal epidermal development, however, the function of these proteins remains elusive. Using an epidermal-specific inducible knockdown mouse model, we demonstrate that ⌬Np63 proteins are essential for maintaining basement membrane integrity and terminal differentiation of keratinocytes. Furthermore, we have identified two ⌬Np63␣ target genes that mediate these processes. We propose that ⌬Np63␣ initially induces expression of the extracellular matrix component Fras1, which is required for maintaining the integrity of the epidermal-dermal interface at the basement membrane. Subsequently, induction of I B kinase-␣ by ⌬Np63␣ initiates epidermal terminal differentiation resulting in the formation of the spinous layer. Our data provide insights into the role of ⌬Np63␣ in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations.

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“…However, it is known that ΔNp63 isoforms can activate the transcription of target genes through a second transactivation domain (18,34). Furthermore, both TAp63α and ΔNp63 can directly or indirectly control the expression of genes that contribute to epidermal differentiation (20,30,31). In the basal layer of stratified epithelia, either in the epidermis or in the esophagus, the predominant p63 isoform is ΔNp63 (35).…”

Section: Resultsmentioning

confidence: 99%

“…Answering this question is important, because p65RelA and p53/p63 have opposing effects on cell growth in mouse primary fibroblasts: p65RelA promotes cell proliferation and inhibits apoptosis (15)(16)(17), whereas p53/ p63 induces apoptosis or senescence (1,18,19). In stratified epithelia, however, both p63 and p65RelA may work together to control epithelial stratification: p63 has been shown to be an upstream regulator of p65RelA, through its ability to induce IKKα expression (20). Furthermore, Wa3 mice, which spontaneously develop wavy hair, have been reported to carry a mutation in the genomic locus that encodes for the iASPP protein, and it has also been proposed that the observed phenotype is caused by a defect in the NFκB pathway (21).…”

mentioning

confidence: 99%

Inhibitor of apoptosis-stimulating protein of p53 (iASPP) prevents senescence and is required for epithelial stratification

Notari

Koch

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is the most ancient member of the ASPP family of proteins and an evolutionarily conserved inhibitor of p53. iASPP is also a binding partner and negative regulator of p65RelA. Because p65RelA and the p53 family members often have opposite effects in controlling cell fate, it is important to understand the cellular context in which iASPP can regulate their activities. To address this question and to study the biological importance of iASPP in vivo, we generated a transgenic mouse in which iASPP expression is controlled by the Cre/loxP recombination system. We observed that iASPP is able to prevent premature cellular senescence in mouse embryonic fibroblasts. iASPP loss resulted in increased differentiation of primary keratinocytes both in vitro and in vivo. In stratified epithelia, nuclear iASPP often colocalized with p63 in the nuclei of basal keratinocytes. Consistent with this, iASPP bound p63 and inhibited the transcriptional activity of both TAp63α and ΔNp63α in vitro and influenced the expression level of p63-regulated genes such as loricrin and involucrin in vivo. In contrast, under the same conditions, p65RelA was frequently expressed as a cytoplasmic protein in the suprabasal layers of stratified epithelia and rarely colocalized with nuclear iASPP. Thus, iASPP is likely to control epithelial stratification by regulating p63's transcriptional activity, rather than p65RelA's. This study identifies iASPP as an inhibitor of senescence and a key player in controlling epithelial stratification.

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p63 is upstream of IKKα in epidermal development

Cited by 107 publications

References 29 publications

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

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

p63 induces key target genes required for epidermal morphogenesis

Inhibitor of apoptosis-stimulating protein of p53 (iASPP) prevents senescence and is required for epithelial stratification

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