Mutational analysis of oncogenes is critical for our understanding of cancer development. Oncogenome screening has identified a fibroblast growth factor receptor 4 (FGFR4) Y367C mutation in the human breast cancer cell line MDA-MB453. Here, we investigate the consequence of this missense mutation in cancer cells. We show that MDA-MB453 cells harbouring the mutation are insensitive to FGFR4-specific ligand stimulation or inhibition with an antagonistic antibody. Furthermore, the FGFR4 mutant elicits constitutive phosphorylation leading to an activation of the mitogen-activated protein kinase cascade as shown by an enhanced Erk1/2 phosphorylation. Cloning and ectopic expression of the FGFR4 Y367C mutant in HEK293 cells revealed high pErk levels and enhanced cell proliferation. Based on these findings, we propose that FGFR4 may be a driver of tumour growth, particularly when highly expressed or stabilized and constitutively activated through genetic alterations. As such, FGFR4 presents an option for further mutational screening in tumours and is an attractive cancer target with the therapeutic potential.

Cervical carcinomas result from cellular transformation by the human papillomavirus (HPV) E6 and E7 oncogenes which are constitutively expressed in cancer cells. The E6 oncogene degrades p53 thereby modulating a large set of p53 target genes as shown previously in the cervical carcinoma cell line HeLa. Here we show that the TAp63β isoform of the p63 transcription factor is also a target of E6. The p63 gene plays an essential role in skin homeostasis and is expressed as at least six isoforms. One of these isoforms, ΔNp63α, has been found overexpressed in squamous cell carcinomas and is shown here to be constitutively expressed in Caski cells associated with HPV16. We therefore explored the role of p63 in these cells by performing microarray analyses after repression of endogenous E6/E7 expression. Upon repression of the oncogenes, a large set of p53 target genes was found activated together with many p63 target genes related to cell adhesion. However, through siRNA silencing and ectopic expression of various p63 isoforms we demonstrated that TAp63β is involved in activation of this cell adhesion pathway instead of the constitutively expressed ΔNp63α and β. Furthermore, we showed in cotransfection experiments, combined with E6AP siRNA silencing, that E6 induces an accelerated degradation of TAp63β although not through the E6AP ubiquitin ligase used for degradation of p53. Repression of E6 transcription also induces stabilization of endogenous TAp63β in cervical carcinoma cells that lead to an increased concentration of focal adhesions at the cell surface. Consequently, TAp63β is the only p63 isoform suppressed by E6 in cervical carcinoma as demonstrated previously for p53. Down-modulation of focal adhesions through disruption of TAp63β therefore appears as a novel E6-dependent pathway in transformation. These findings identify a major physiological role for TAp63β in anchorage independent growth that might represent a new critical pathway in human carcinogenesis.

A mitochondrial-derived peptide regulates nuclear gene expression in response to metabolic stress.

A Wnt ligand acting through a receptor tyrosine kinase restricts neuromuscular junctions to the central muscle zone.