Frequent gain of thep40/p51/p63 gene locus in primary head and neck squamous cell carcinoma

Yamaguchi, Kengo; Li, Wu; Caballero, Otávia L.; Hibi, Kenji; Trink, Barry; Resto, Vicente A.; Cairns, Paul; Okami, Kenji; Koch, Wayne M.; Sidransky, David; Jen, Jin

doi:10.1002/(sici)1097-0215(20000601)86:5<684::aid-ijc13>3.0.co;2-m

Cited by 112 publications

(91 citation statements)

References 17 publications

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“…32,[41][42][43][44][45][46] Further support for this relationship is evidenced by the negative effect of ⌬N isoform transfection on the p53 endogenous transcriptional activity and by increased tumor size in rats. 47,48 Other studies 45,49 -51 have also reported a p53 independent tumorigenic role for the ⌬Np63 isoform in dermal and head and neck squamous epithelium. Together, these results suggest that ⌬Np63 may regulate stem and/or myoepithelial cells through a dominant negative effect on the TAp63, leading to the induction of cell senescence and suppressor functions.…”

Section: Discussionmentioning

confidence: 89%

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: Discussionmentioning

confidence: 89%

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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“…It is possible that p63 gene amplification may be the cause of p63 over-expression as amplification has been detected in some squamous cell cancers of the head and neck and lung. 21,22 However as giant cells form by fusion of mononuclear cells 23,24 if the p63 gene was amplified it would be expected that the p63 mRNA levels in the giant cells would be similar to those in mononuclear cells. This suggests that gene amplification is likely not the cause of p63 overexpression in these tumors but it will be necessary to confirm this by determining p63 gene copy number.…”

Section: Discussionmentioning

confidence: 99%

Giant cell tumor of bone express p63

Dickson

Wunder

et al. 2008

Modern Pathology

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p63 contributes to skeletal development and tumor formation; however, little is known regarding its activity in the context of bone and soft tissue neoplasms. The purpose of this study was to investigate p63 expression in giant cell tumor of bone and to determine whether it can be used to discriminate between other giant cell-rich tumors. Seventeen cases of giant cell tumor of bone were examined to determine the cell type expressing p63 and identify the isoforms present. Total RNA or cell protein was extracted from mononuclear-or giant cellenriched fractions or intact giant cell tumor of bone and examined by RT-PCR or western blot, respectively. Immunohistochemistry was used to evaluate p63 expression in paraffin embedded sections of giant cell tumor of bone and in tumors containing multinucleated giant cells, including: giant cell tumor of tendon sheath, pigmented villonodular synovitis, aneurysmal bone cyst, chondroblastoma, and central giant cell granuloma. The mononuclear cell component in all cases of giant cell tumor of bone was found to express all forms of TAp63 (a, b, and c), whereas only low levels of the TAp63 a and b isoforms were detected in multinucleated cells; DNp63 was not detected in these tumors. Western blot analysis identified p63 protein as being predominately localized to mononuclear cells compared to giant cells. This was confirmed by immunohistochemical staining of paraffin-embedded tumor sections, with expression identified in all cases of giant cell tumor of bone. Only a proportion of cases of aneurysmal bone cyst and chondroblastoma showed p63 immunoreactivity whereas it was not detected in central giant cell granuloma, giant cell tumor of tendon sheath, or pigmented villonodular synovitis. The differential expression of p63 in giant cell tumor of bone and central giant cell granuloma suggest that these two tumors may have a different pathogenesis. Moreover, p63 may be a useful biomarker to differentiate giant cell tumor of bone from central giant cell granuloma and other giant cell-rich tumors, such as giant cell tumor of tendon sheath and pigmented villonodular synovitis.

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“…FaDu cells derived from a hypopharyngeal squamous cell carcinoma Transcriptional activation of MFGE8 by p63 T Okuyama et al (Yamaguchi et al, 2000), HSC-1 from a skin squamous cell carcinoma and NHK were 'p63-positive': the TA, DN, a/b and g mRNA sequences were detected by RT-PCR, and TAp63a (85 kDa), DNp63a (75 kDa), TAp63g (57 kDa) and DNp63g (47 kDa) by western blotting. HEK293 cells were negative for p63 mRNAs and proteins: the TA and DN isoform mRNAs were 4-fold and 32-fold less in HEK293, respectively.…”

Section: Transcriptional Activation Of Mfge8 By P63 T Okuyama Et Almentioning

confidence: 99%

p63(TP63) elicits strong trans-activation of the MFG-E8/lactadherin/BA46 gene through interactions between the TA and ΔN isoforms

et al. 2007

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We report here that human MFGE8 encoding milk fat globule-EGF factor 8 protein (MFG-E8), also termed 46 kDa breast epithelial antigen and lactadherin, is transcriptionally activated by p63, or TP63, a p53 (TP53) family protein frequently overexpressed in head-and-neck squamous cell carcinomas, mammary carcinomas and so on. Despite that human MFG-E8 was originally identified as a breast cancer marker, and has recently been reported to provide peptides for cancer immunotherapy, its transcriptional control remains an open question. Observations in immunohistochemical analyses, a tetracycline-induced p63 expression system and keratinocyte cultures suggested a physiological link between p63 and MFGE8. By reporter assays with immediately upstream regions of MFGE8, we determined that the trans-activator (TA) isoforms of p63 activate MFGE8 transcription though a p53/p63 motif at À370, which was confirmed by a chromatin immunoprecipitation experiment. Upon siRNAmediated p63 silencing in a squamous cell carinoma line, MFG-E8 production decreased to diminish Saos-2 cell adhesion. Interestingly, the DN-p63 isoform lacking the TA domain enhanced the MFGE8-activating function of TA-p63, if DN-p63 was dominant over TA-p63 as typically observed in undifferentiated keratinocytes and squamous cell carcinomas, implying a self-regulatory mechanism of p63 by the TA:DN association. MFG-E8 may provide a novel pathway of epithelial-nonepithelial cell interactions inducible by p63, probably in pathological processes.

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Frequent gain of thep40/p51/p63 gene locus in primary head and neck squamous cell carcinoma

Cited by 112 publications

References 17 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

Giant cell tumor of bone express p63

p63(TP63) elicits strong trans-activation of the MFG-E8/lactadherin/BA46 gene through interactions between the TA and ΔN isoforms

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