HMGA2 expression is regulated by the let-7 miRNA
An Interview with
Christine Mayr "I became fascinated by what essentially was a new gene regulatory mechanism" 
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HMGA2 is a paradigm for an oncogene being overexpressed due to loss of its miRNA binding sites (Mayr et al., 2007). It is regulated by the let-7 family of miRNAs, which bind to the 3'UTR of the HMGA2 transcript. These binding sites are lost due to chromosomal translocations in a wide variety of human tumors. Loss of regulation by let-7 leads to protein overexpression of HMGA2 and to oncogenic transformation.
MiRNA regulation might be lost in a number of ways, and we showed that one mechanism is APA.
Gene expression is regulated by changes in 3'UTR length
Differential use of APA sites can lead to changes in 3'UTR length with loss (or gain) of regulatory sequences thereby influencing gene expression. Recently, it has been shown that shortening or lengthening of 3'UTRs is used as a means for regulation of gene expression in diverse biological processes. These processes include T cell activation, neuronal depolarization, proliferation and differentiation during embryonic development, as well as oncogenic transformation (Mayr & Bartel, 2009). It seems that proliferating, immature and transformed cells have mRNAs with shorter 3'UTRs whereas terminally differentiated cells mostly have mRNAs with full-length 3'UTRs allowing a tighter regulation.
Selected Publications
Mayr C & Bartel DP. Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell, in press.
Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470-476 (2008). Epub 2008 Nov 2.
Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315, 1576-1579 (2007). Epub 2007 Feb 22.
Lab Head CV (PDF)
