Relationships between p63 Binding, DNA Sequence, Transcription Activity, and Biological Function in Human Cells

Yang, Annie; Zhu, Zhou; Kapranov, Philipp; McKeon, Frank; Church, George M.; Gingeras, T; Struhl, Kevin

doi:10.1016/j.molcel.2006.10.018

Cited by 260 publications

(322 citation statements)

References 44 publications

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“…Through the use of RNAi inactivation coupled to gene expression profiling and ChIP on chip, several labs have recently identified hundreds of p63 targets. 6,[11][12][13][14] Specifically, procaspase-8 emerged in the RNAi profiling of human HaCat cells as a gene regulated by p63. 14 Caspases are an evolutionarily conserved family of aspartate-specific cystein-dependent proteases involved in apoptosis, as well as in inflammation.…”

mentioning

confidence: 99%

p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis

et al. 2008

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The transcription factor p63, member of the p53 family, is crucial for epithelial development. An RNAi screening identified the apoptotic gene Procaspase-8 as a target activated by p63. The caspase-8 inhibitor FLIP is also under p63 control. We analysed and detailed the direct transactivation through the use of RNAi, reporter assays, ChIPs, western blots, confocal studies in HaCat, as well as in primary human keratinocytes. The direct DNp63 regulation of these targets was confirmed in vivo using transgenic DNp63 mice under the K5 promoter, as compared with p63 knockout mice, and in vitro in normal human primary keratinocytes following UV irradiation. Lowering the steady state of p63 protein levels changes the relative ratio of FLIP isoforms, causing the activation of the expressed, inactive Procaspase-8, into the active isoform thus triggering the proapoptotic cascade. Therefore, p63 fine-tunes the Procaspase-8-FLIP pro-and antiapoptotic pathway in keratinocytes.

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confidence: 99%

p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis

et al. 2008

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“…In contrast, Ortt and Sinha (2006) concluded that the optimal p63 DNA-binding motif contains a half-site with central core sequence CATG similar to p53's, but differs by having AT-rich 5 0 and 3 0 sequences flanking it. A third study found two direct repeats resembling the p53 consensus sequence but of unique length and sequence composition (Yang et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

“…Associated cis-elements for other transcription factors could mediate cooperative binding (Yang et al, 2006). Studies addressing the binding-site preferences for p73 could also provide insight to the intricate regulatory networks within the p53 family.…”

Section: Discussionmentioning

confidence: 99%

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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“…Indeed, beyond its dominantnegative effect on p53 suppressor function, DNp63 was found to favour angiogenesis and chemoresistance (Senoo et al, 2002;Wu et al, 2005;Rocco et al, 2006) and to regulate cell-adhesion processes (Carroll et al, 2006;Yang et al, 2006). Conversely, several studies reported a loss of p63 expression in metastatic stages (Barbieri et al, 2006;Adorno et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

et al. 2011

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The DNp63 protein, a product of the TP63 gene that lacks the N-terminal domain, has a critical role in the maintenance of self renewal and progenitor capacity in several types of epithelial tissues. DNp63 is frequently overexpressed in squamous cell carcinoma (SCC) and in some other epithelial tumours. This overexpression may contribute to tumour progression through dominantnegative effects on the transcriptionally active (TA) isoforms of the p53 family (TAp63, TAp73 and p53), as well as through independent mechanisms. However, the molecular basis of DNp63 overexpression is not fully understood. Here, we show that the expression of DNp63 is regulated by the Wnt/b-catenin pathway in human hepatocellular carcinoma (HCC) and SCC cell lines. This regulation operates in particular through TCF/LEF sites present in the P2 promoter of TP63. In addition, we show that DNp63 and b-catenin are frequently coexpressed and accumulated in oesophageal SCC, but not in HCC. These results suggest that activation of the b-catenin pathway may contribute to overexpression of DNp63 during tumour progression, in a cell type-specific manner.

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Relationships between p63 Binding, DNA Sequence, Transcription Activity, and Biological Function in Human Cells

Cited by 260 publications

References 44 publications

p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis

p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis

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

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

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