Endogenous p63 acts as a survival factor for tumour cells of SCCHN origin

Thurfjell, Niklas; Coates, Philip J.; Vojtesek, Borek; Benham-Motlagh, Parvis; Eisold, Michael; Nylander, Karin

doi:10.3892/ijmm.16.6.1065

Cited by 23 publications

(38 citation statements)

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“…These results should also be considered in relation to the effects of ΔNp63 in promoting cell survival, which presents an apparent paradox to the sensitivity of p63-expressing breast and HNSCC tumors to cisplatin. Indeed, in HNSCC, siRNA-mediated reduction in the endogenous p63 levels results in more tumor cells being killed by radiation and cisplatin, demonstrating a pro-survival role for p63 [89]. These contradictory data indicate that although the expression of ΔNp63 in tumors leads to enhanced survival, cisplatin is most effective in ΔNp63-positive tumors precisely because this agent targets ΔNp63 for degradation and thereby removes a critical survival factor in addition to acting as a highly genotoxic agent.…”

Section: Tumor Suppressor or Oncogenic Role? Crosstalk Between P53 Famentioning

confidence: 84%

The role of P63 in cancer, stem cells and cancer stem cells

Nekulova

Holcakova

Coates

et al. 2011

Cellular and Molecular Biology Letters

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The transcription factor p63 has important functions in tumorigenesis, epidermal differentiation and stem cell self-renewal. The TP63 gene encodes multiple protein isoforms that have different or even antagonistic roles in these processes. The balance of p63 isoforms, together with the presence or absence of the other p53 family members, p73 and p53, has a striking biological impact. There is increasing evidence that interactions between p53-family members, whether cooperative or antagonistic, are involved in various cell processes. This review summarizes the current understanding of the role of p63 in tumorigenesis, metastasis, cell migration and senescence. In particular, recent data indicate important roles in adult stem cell and cancer stem cell regulation and in the response of cancer cells to therapy.

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Section: Tumor Suppressor or Oncogenic Role? Crosstalk Between P53 Famentioning

confidence: 84%

The role of P63 in cancer, stem cells and cancer stem cells

Nekulova

Holcakova

Coates

et al. 2011

Cellular and Molecular Biology Letters

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“…These cells have mutated p53 protein and have a similar p63 expression profile to primary human SCCHN tumors. 14,15 DNp63a is the main isoform expressed in these cells which could be detected both at protein and mRNA levels. TAp63 isoforms, however, could be detected only at mRNA level.…”

Section: Decreased Traf4 Expression In P63-disrupted Scchn Cellsmentioning

confidence: 99%

“…Importantly, reducing the endogenous level of p63 in SCCHN cells leads to reduced viability and enhances the response to chemo-and radio-therapy. 15 Tumor necrosis factor receptor (TNFR) associated factors (TRAFs) are a family of adapter proteins involved in signal transduction by members of the TNFR and IL1/Toll receptor family, and TRAF4 is the most distinct member of the TRAF family. [16][17][18] Unlike other TRAF knock-out mice, TRAF4 deficient mice show defects in neural tube closure as well as defects in the upper respiratory tract and axial skeleton.…”

Section: Introductionmentioning

confidence: 99%

TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHN

Coates²,

MacCallum³

et al. 2007

Cancer Biology & Therapy

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AbstrActp63, a member of the p53 family, is overexpressed in squamous cell carcinoma of the head and neck (SCCHN) and some other tumors of epithelial origin. As a transcription factor, p63 can bind to p53-type response elements and there is some overlap between p53 family transcriptional targets. Tumor necrosis factor receptor associated factor 4 (TRAF4) is a p53 regulated gene which is overexpressed in many human carcinomas. We investigated the involvement of p63 in regulation of TRAF4 and the expression of the TRAF4 protein in SCCHN. Disrupting endogenous p63 expression resulted in downregulation of TRAF4 mRNA and protein in an SCCHN cell line. Endogenous p63 bound to the TRAF4 promoter in vivo and reporter assays showed that p63, p73 and p53 can all transactivate TRAF4, with TAp63 isoforms being the most potent activators. The level of TRAF4 activation by TAp63 was two-fold higher than by p53, and TRAF4 was ten-fold more responsive to TAp63 than another p63-target, IGFBP3. Nuclear expression of TRAF4 was seen in normal oral epithelium and highly/moderately differentiated SCCHN, whereas cytoplasmic expression of TRAF4 was seen in poorly differentiated SCCHN. These results indicate that TRAF4 is a common target of p53 family members and that localization of TRAF4 is associated with differentiation of SCCHN cells.

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“…[3][4][5] Although the precise role of p63 in human squamous cell carcinomas is not known, inhibition of p63 in SCCHN cells in vitro implies a major role in maintaining survival and/or inhibiting normal differentiation processes, rather than stimulating cell proliferation. 6 Wound healing represents a well-characterized process in which cell migration, proliferation and differentiation are altered in a series of ordered steps to repair the injury. In oral wound healing the wound surface is quickly covered by an epithelial "tongue" formed by the adjacent nonwounded epithelium with migrating basal cells and a sliding epithelial mass above those.…”

Section: Downregulation Of Tap63 and Unaffected Levels Of P63β Distinmentioning

confidence: 99%

“…(C) Summary of changes in p63 isoform mRNA levels in oral wounds and our previous data from SCCHN tumours. 6 In each case, samples are compared with corresponding normal tissue from the same patient. Only changes marked with "*" are statistically significant.…”

Section: Downregulation Of Tap63 and Unaffected Levels Of P63β Distinmentioning

confidence: 99%