Potential overlapping functions of TGF-β and p53 in microRNA processing. Smads and p53 act to increase the posttranscriptional maturation of a subset of miRNAs via direct binding of the DROSHA-associated helicase p68 [49–52]. These miRNAs have crucial roles in tumour suppression acting in cytostasis and DNA repair. Interestingly pro-survival miRNAs are also upregulated indicating a possible mechanism for protumourigenesis by inhibition of key tumour suppressors. However, upregulation of these prosurvival miRNAs may also facilitate the induction of senescence, protecting cells from cell death induced by tumour suppressor genes. In addition to acting as a molecular tag to direct DROSHA activity binding of Smads and p53 may act to promote p68 helicase activity, which could act to induce conformational changes in pri-miRNA structure making it accessible for DROSHA cleavage. As proposed by Davis et al. competition may occur between Smads and p53 for binding to p68 upon which binding of one protein results in the inhibition of p68 association with other [51]. Binding of Smads to microRNAs is mediated by association with CAGAC Smad DNA-binding-like elements (SBEs) and a similar p53 response-element- (RE) mediated mechanism may also occur for p53. Potential RE and SBE sequence overlap may also occur adding a potential further layer of cross-regulation.
