High level expression of ΔN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)?

Crook, Tim; Nicholls, John M.; Brooks, Lucy; O’Nions, Jenny; Allday, Martin J.

doi:10.1038/sj.onc.1203656

Cited by 186 publications

(169 citation statements)

References 37 publications

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“…Salivary duct and acinic cell carcinomas, tumors that lack myoepithelial and/or basal cells, were deficient for both isoforms. Our findings are in agreement with previous studies 11,16 of salivary tumors and indicate a dominant role for the ⌬Np63 isoform in salivary gland tumorigenesis. Moreover, the re- stricted expression of the p63 to tumors with myoepithelial and/or basal cells indicates that these elements are critically important in both mammary and certain salivary gland development and pathogenesis.…”

Section: Discussionsupporting

confidence: 83%

“…[15][16][17][18] p63 -/-mice have striking developmental defects, including complete lack of all stratified squamous epithelia, epidermal appendages, and mammary, lacrimal, and salivary glands, supporting an important role in the development and differentiation of these organs. 19 -26 The TP63 gene encodes for six isoforms that contain (TA) or lack (⌬N) the transactivation domain because of the use of two different promoters and three alternative splices of the C-terminal end ( Figure 1A).…”

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confidence: 99%

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Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Mitani

Weber

et al. 2011

The American Journal of Pathology

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The TP63 gene, a TP53 homologue, encodes for two main isoforms by different promoters: one retains (TA) and the other lacks (⌬N) the transactivation domain. p63 plays a critical role in the maintenance of basal and myoepithelial cells in ectodermally derived tissues and is implicated in tumorigenesis of several neoplastic entities. However, the biological and regulatory roles of these isoforms in salivary gland tumorigenesis remain unknown. Our results show a reciprocal expression between TA and ⌬N isoforms in both benign and malignant salivary tumors. The most dominantly expressed were the ⌬N isoforms, whereas the TA isoforms showed generally low levels of expression, except in a few tumors. High ⌬Np63 expression characterized tumors with aggressive behavior, whereas tumors with high TAp63 expression were significantly smaller and less aggressive. In salivary gland cells, high expression of ⌬Np63 led to enhanced cell migration and invasion and suppression of cell senescence independent of TAp63 and/or TP53 gene status. We conclude the following: i) overexpression of ⌬Np63 contributes to salivary tumorigenesis, ii) ⌬Np63 plays a dominant negative effect on the TA isoform in the modulation of cell migration and invasion, and iii) the ⌬N isoform plays an oncogenic role and may represent an attractive target for therapeutic intervention in patients with salivary carcinomas.

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Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Mitani

Weber

et al. 2011

The American Journal of Pathology

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“…1 Apparently, other events such as overexpression of the DeltaNp63 gene may be involved in the immortalization of nasopharyngeal epithelial cells. 25 Moreover, the homozygous deletion at 9p21 in NP460 hTert cells may lead to loss of p14/ARF, which may play important regulatory role in p53 ubiquitination. 26 Another event observed in the emerging clones from the senescing population of NP460hTert is the expression of Id1.…”

Section: Discussionmentioning

confidence: 99%

Molecular and cytogenetic changes involved in the immortalization of nasopharyngeal epithelial cells by telomerase

Man

Jin

et al. 2006

Intl Journal of Cancer

111

136

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Nasopharyngeal carcinoma (NPC) is a common disease in Hong Kong and southern provinces of China. EBV infection is believed to play a critical role in the development of NPC. Previous studies on the transformation mechanism of EBV genes were mostly performed in either NPC or nonnasopharyngeal epithelial cells which may not be representative of premalignant nasopharyngeal epithelial cells. Establishment of a representative cell system would greatly facilitate the elucidation of the role of EBV infection in the development of NPC. Using telomerase alone, we were able to establish an immortalized nasopharyngeal epithelial cell line from primary nonmalignant nasopharyngeal biopsies. The telomerase‐immortalized nasopharyngeal epithelial cells are largely diploid in karyotype. Interestingly, this newly immortalized nasopharyngeal epithelial cell line, referred as NP460hTert, harbors genetic alterations previously identified in premalignant and malignant nasopharyngeal epithelial cells. These include inactivation of p16 by homozygous deletion of the p16INK4A locus and downregulation of RASSF1A expression. The deletion of the p16INK4A locus appears to be the most crucial event for the immortalization of nasopharyngeal epithelial cells by telomerase and precedes RASSF1A downregulation. In addition, detailed analysis of the cytogenetic changes by conventional cytogenetics, spectral karyotyping (SKY) and array‐based CGH revealed a gain of a 17q21‐q25 fragment on 11p15 chromosome in all NP460hTert cells which occurred before deletion of the p16INK4A locus. Gain of 17q has been previously reported in NPC. In addition, activation of NF‐κB was observed in immortalized NP460hTert cells at the later population doublings, and may play a role in the survival of immortalized NP epithelial cells. Id1 which is commonly expressed in various human cancers, including NPC, was also upregulated in the immortalized NP460hTert cells. Thus, the establishment of an immortalized nasopharyngeal epithelial cell line harboring common genetic alterations present in premalignant and cancerous nasopharyngeal epithelial cells may provide a valuable cell system to examine for early events involved in NPC carcinogenesis, particularly in elucidating the role of EBV infection in NPC development. © 2006 Wiley‐Liss, Inc.

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“…p51 not only resembles p53 structurally but also functionally; it acts as a transcription factor capable of inducing apoptosis and growth arrest. Furthermore, its deregulated expression is frequently observed in a subset of human epithelial cancers and it is also shown to play definitive roles in tumor suppression (Crook et al, 2000;Hibi et al, 2000;Park et al, 2000;Cui et al, 2005).…”

mentioning

confidence: 99%

“…Specific expression of DNp51B/DNp63a isoform in basal keratinocytes (Yang et al, 1998;Parsa et al, 1999) and overexpression of this isoform in a range of squamous cell carcinomas suggest growth promoting potential of this isoform (Crook et al, 2000;Hibi et al, 2000;Park et al, 2000;Cui et al, 2005). Despite this obvious importance of p51, its exact roles in these processes are largely unknown.…”

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confidence: 99%

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

et al. 2007

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High level expression of ΔN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)?

Cited by 186 publications

References 37 publications

Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Molecular and cytogenetic changes involved in the immortalization of nasopharyngeal epithelial cells by telomerase

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

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