Apoptosis induction by the stem factor Lin28A

Lin28A/B are highly conserved RNA binding proteins that regulate gene expression by repressing the maturation of let-7 microRNA or by binding directly to mRNAs. Normally, Lin28A/B are expressed in stem and progenitor cells where they play an important role in stem cells biology. When ectopically expressed Lin28A/B may result in tumor formation. In addition, we have found previously that Lin28A overexpression in adult mouse kidney leads to the formation of cystic kidneys. To study the effect of Lin28A overexpression on kidney cells in-vitro, we introduced a Lin28A inducible overexpression cassette into a mouse kidney cell line (mIMCD3). To our surprise, we found that Lin28A overexpression significantly decreased the cell number in this cell line. Farther testing showed that this phenotype was due to elevated apoptosis. In order to test if this unpredicted phenomenon is unique to mIMCD-3 cells we tested other kidney human cell lines, HK-2 and HEK-293T. Notably, Lin28A overexpression in these cell lines did not result in apoptosis induction. Next, using Let-7 mimic strategy we explored whether the apoptosis in mIMCD-3 cells occurs through a let-7 dependent or independent mechanism, and found that it is Let-7 independent. This conclusion is further supported by our observation that Lin28B overexpression in mIMCD3 which also led to Let-7 down-regulation didn’t lead to increased apoptosis. Overall, our results show for the first time an apoptosis effect of Lin28A expression. Unraveling the molecular mechanism underlying this phenomenon may have critical applications both in stem cells and in cancer biology.