p53 is the most frequently inactivated gene in human cancers, reflecting its pivotal role in maintaining genomic integrity. The present study was conducted to explore the possibility that tumour cells with no intrinsic defects of the p53 pathway might nevertheless acquire p53 dysfunction through extrinsic suppression of the pathway by microenvironmental factors. Neoplastic cells from patients with chronic lymphocytic leukaemia (CLL) were cultured in the presence or absence of basic fibroblast growth factor (bFGF) and exposed to ionizing radiation (IR) to induce p53 accumulation. bFGF is greatly increased in the plasma of CLL patients and can suppress p53 activation in some experimental models. IR induced a marked increase in p53 levels in 28 samples from 24 patients. bFGF inhibited IR-induced p53 accumulation to some extent in most of these samples and by more than 50% in seven samples from seven patients. Suppression of p53 activation by bFGF was frequently but not always accompanied by upregulation of the p53-inhibitory protein MDM2 and/or phosphorylation of MDM2 at serine 166, and was associated with impaired transcriptional activation of the p53 target gene p21. These observations provide the first demonstration in human cancer cells that the p53 pathway can be suppressed by factors in the tumour-cell microenvironment.
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Thanks are due to Mr Anthony Carter for his help with FACS analysis. The work was supported by grants from the UK Leukaemia Research Fund and the Royal Liverpool and Broadgreen University Hospitals R&D Support Fund.
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Romanov, V., James, C., Sherrington, P. et al. Basic fibroblast growth factor suppresses p53 activation in the neoplastic cells of a proportion of patients with chronic lymphocytic leukaemia. Oncogene 24, 6855–6860 (2005). https://doi.org/10.1038/sj.onc.1208895
- basic fibroblast growth factor (bFGF)
- chronic lymphocytic leukaemia (CLL)
Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells