Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Sayan, A. E.; Stanford, R.; Vickery, R.; Grigorenko, E.; Diesch, J.; Kulbicki, K.; Edwards, R.; Pal, R.; Greaves, P.; Jariel-Encontre, I.; Piechaczyk, M.; Kriajevska, M.; Mellon, J. K.; Dhillon, A. S.; Tulchinsky, E.


2012-03-22 / vol 31 / pages 1493-503


Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscle-invasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.

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1476-5594 (Electronic) 0950-9232 (Linking)


Cell Line, Tumor; Humans; Cell Proliferation; Transcriptional Activation; Phosphorylation; Proto-Oncogene Proteins c-fos/*metabolism; Up-Regulation; Cell Movement/*genetics; Cell Shape/drug effects; Gene Expression Regulation, Neoplastic; Proto-Oncogene Proteins/*metabolism; Receptor Protein-Tyrosine Kinases/*metabolism; Urinary Bladder Neoplasms/*genetics

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