Mutant p53 regulates Dicer through p63-dependent and -independent mechanisms to promote an invasive phenotype.
The control and processing of microRNAs (miRs) is critical in the regulation of all cellular responses. Previous studies have suggested that a reduction in the expression of certain miRs, or an overall decrease in miR processing through the partial depletion of Dicer, can promote enhanced metastatic potential. We show here that Dicer depletion can promote the invasive behavior of cells that is reflected in enhanced recycling and activation of the growth factor receptors Met and EGF receptor. These responses are also seen in response to the expression of tumor-derived mutant p53s, and we show that mutant p53 can down-regulate Dicer expression through both direct inhibition of the TAp63-mediated transcriptional activation of Dicer and a TAp63-independent control of Dicer protein expression. Our results delineate a clear relationship between mutant p53, TAp63, and Dicer that might contribute to the metastatic function of mutant p53 but, interestingly, also reveal TAp63-independent functions of mutant p53 in controlling Dicer activity.
From the Cancer Research UK Beatson Institute, Glasgow G61 1BD, Scotland, United Kingdom and.
Patricia A J
PA
Muller
Antonio G
AG
Trinidad
Patrick T
PT
Caswell
Jim C
JC
Norman
Karen H
KH
Vousden
D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D043244:Ribonuclease III / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
Cell Invasion; Cell Motility; Cell Scattering; Dicer; MicroRNA; Mutant p53; p63