p63 and p73 Transactivate Differentiation Gene Promoters in Human Keratinocytes

Laurenzi, Vincenzo De; Rossi, Antonello; Terrinoni, Alessandro; Barcaroli, Daniela; Levrero, Massimo; Costanzo, Antonio; Knight, Richard; Guerrieri, Pietro; Melino, Gerry

doi:10.1006/bbrc.2000.2932

Cited by 122 publications

(114 citation statements)

References 36 publications

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“…Although the expression level of p63 is much higher, some cells of the basal layer as well as in the hair follicle express p73 as well. This observation is consistent with earlier reports of p73 expression in the skin 11,13,14 as well as in multiciliated cells. 15 To further investigate if cells exist that simultaneously express both p63 and p73, we used immunofluorescence (IF).…”

Section: Resultssupporting

confidence: 94%

“…Both proteins also occur simultaneously in normal tissues such as the basal layer of keratinocytes. 9,11 As a first step to characterize the biological function of such hetero-tetramers, we wanted to investigate if they exist in human primary keratinocytes. In addition, we were interested to understand at the structural level exactly why the hetero-tetramer is thermodynamically more stable than the homo-tetramers and how this interaction contributes to the inhibition of TAp73β in HNSCCs.…”

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confidence: 99%

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Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization

et al. 2016

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Members of the p53 tumor-suppressor family are expressed as multiple isoforms. Isoforms with an N-terminal transactivation domain are transcriptionally active, while those ones lacking this domain often inhibit the transcriptional activity of other family members. In squamous cell carcinomas, the high expression level of ΔNp63α inhibits the tumor-suppressor function of TAp73β. This can in principle be due to blocking of the promoter or by direct interaction between both proteins. p63 and p73 can heterooligomerize through their tetramerization domains and a hetero-tetramer consisting of two p63 and two p73 molecules is thermodynamically more stable than both homo-tetramers. Here we show that cells expressing both p63 and p73 exist in mouse epidermis and hair follicle and that hetero-tetramer complexes can be detected by immunoprecipitation in differentiating keratinocytes. Through structure determination of the hetero-tetramer, we reveal why this hetero-tetramer is the thermodynamically preferred species. We have created mutants that exclusively form either hetero-tetramers or homo-tetramers, allowing to investigate the function of these p63/p73 hetero-tetramers. Using these tools, we show that inhibition of TAp73β in squamous cell carcinomas is due to promoter squelching and not direct interaction.

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Section: Resultssupporting

confidence: 94%

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confidence: 99%

Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization

et al. 2016

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“…43 Further evidence for a role in cellular differentiation suggests that TAp73g and TAp73d may be involved in the terminal differentiation of human skin keratinocytes. 44 Mice, functionally deficient for all p73 isoforms, exhibited profound defects, including hippocampal dysgenesis, hydrocephalus, chronic infections and inflammation, as well as abnormalities in pheromone sensory pathways, however, did not show any increase susceptibility to cancer. 45 The p73-deficient male mice lacked both interest in sexually mature females and aggressive responses to other males.…”

Section: P63 and Cancermentioning

confidence: 97%

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

2006

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Abstractp63, p73 and p53 compose a family of transcription factors involved in cell response to stress and development. p53 is the most frequently mutated gene in cancer (50%) and loss of p53 activity is considered to be ubiquitous to all cancers. Recent publications may have a profound impact on our understanding of p53 tumour suppressor activity. p63, p73 and p53 genes have a dual gene structure conserved in drosophila, zebrafish and man. They encode for multiple p63, p73 or p53 proteins containing different protein domains (isoforms) due to multiple splicing, alternative promoter and alternative initiation of translation. In this review, we describe the different isoforms of p63, p73, p53 and their roles in development and cancer. The changes in the interactions between p53, p63 and p73 isoforms are likely to be fundamental to our understanding in the transition between normal cell cycling and the onset of tumour formation. Cell Death and Differentiation (2006) Introduction p53 was discovered in 1979 as a protein interacting with the oncogenic T antigen from SV40 virus. 1-5 p53 protein is the product of a pivotal tumor-suppressor gene whose inactivation by mutation or interaction with viral or overexpressed cellular proteins occurs in almost all cancers. 6 The p53 protein integrates multiple cellular stress signals assessing cellular damages to trigger either cell-cycle arrest or programmed cell death (apoptosis). 7 These effects are predominantly due to p53's ability to bind DNA through p53-responsive element (p53RE) 8,9 and regulate the transcription of genes involved in these processes, such as p21 10 (cell cycle arrest), Puma 11 or Scotin 12 (apoptosis). Thereby, p53 prevents proliferation of genetically abnormal cells and thus cancer formation.Two p53-related genes, p63 and p73, were identified in 1997. 13,14 The high level of sequence similarity between p63, p73 and p53 proteins, particularly in the DNA binding domain, allows p63 and p73 to transactivate p53-responsive genes causing cell cycle arrest and apoptosis. Therefore, p63, p73 and p53 genes form a family of transcription factor. However, they are not functionally entirely redundant and the primary role of each p53 family member -as determined by transgenetic knockout mice -illustrates that each protein has its own unique functions.We recently published that the p53 gene family has a dual gene structure conserved from drosophila to man. 15 Like most of the genes in the human genome, 16 p53 gene family members express multiple mRNA variants due to multiple splicing and alternative promoters. Hence, p53 gene family members express different forms of p53 protein containing different domain of the protein (isoforms). In this review, we will summarise the different isoforms of p63, p73 and p53 expressed in human, mouse and drosophila. p63The mouse p63 gene is composed of 15 exons spanning over 208 000 bp (GenBank Accession Number: AF533892) on chromosome 16, while the human p63 gene is composed of 15 exons, spanning over 270 000 bp on chromosome 3q2...

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“…As in the case of p63, overexpression of p73 in keratinocytes results in promoter activation of loricrin, involucrin and transglutaminase I (TG1). 42 However, developmental defects in p73-deficient mice are related to neuronal differentiation and not to skin abnormalities. 43 In summary, members of the p53 transcription factor family play vital roles in signal transduction leading towards apoptosis and keratinocyte differentiation.…”

Section: Transcription Factors P53 Familymentioning

confidence: 99%

Death penalty for keratinocytes: apoptosis versus cornification

et al. 2005

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Homeostasis implies a balance between cell growth and cell death. This balance is essential for the development and maintenance of multicellular organisms. Homeostasis is controlled by several mechanisms including apoptosis, a process by which cells condemned to death are completely eliminated. However, in some cases, total destruction and removal of dead cells is not desirable, as when they fulfil a specific function such as formation of the skin barrier provided by corneocytes, also known as terminally differentiated keratinocytes. In this case, programmed cell death results in accumulation of functional cell corpses. Previously, this process has been associated with apoptotic cell death. In this overview, we discuss differences and similarities in the molecular regulation of epidermal programmed cell death and apoptosis. We conclude that despite earlier confusion, apoptosis and cornification occur through distinct molecular pathways, and that possibly antiapoptotic mechanisms are implicated in the terminal differentiation of keratinocytes.

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p63 and p73 Transactivate Differentiation Gene Promoters in Human Keratinocytes

Cited by 122 publications

References 36 publications

Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization

Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

Death penalty for keratinocytes: apoptosis versus cornification

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