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Extracellular Signal-regulated Kinases Phosphorylate Lin28a Protein to Modulate P19 Cell Proliferation and Differentiation

Mar 20, 2017     Email"> PrintText Size

Proliferation and differentiation are tightly coupled processes for stem cells which are regulated by signals from extracellular environment. Among these signals, MAPK-ERK signaling pathway plays an important role in controlling cell proliferation in most somatic cells. Activation or prolongation of MAPK signaling often induces differentiation, then connects cell proliferation and development events. 

Lin28a, originally discovered in the nematode Caenorhabditis elegans and highly conserved across species, is implicated in cell proliferation and pluripotency control. By directly binding to its target RNAs, Lin28a is known to inhibit maturation of let-7 miRNA family and promotes their turnover, thereby influencing an army of let-7 targets including Lin28a itself, which are master regulators of cell proliferation and the pluripotent status of stem cells.

A research team led by Dr. GAO Daming at Shanghai Institute of Biochemistry and Cell Biology of Chinese Academy of Sciences (CAS) recently revealed a new regulatory mechanism connecting extra-cellular signal and micro-RNA function. This study was published in Journal of Biological Chemistry. 

By editing lin28a gene with the CRISPR/Cas9-based method, P19 mouse embryonic carcinoma (EC) stem cells expressing Lin28a-S200A (phospho-deficient) and Lin28a-S200D (phospho-mimetic) mutants were generated by researchers to study the functional impact of Ser-200 phosphorylation.

Lin28a-S200D-expressing cells, but not Lin28a-S200A-expressing or control P19 EC stem cells, displayed impaired inhibition of let-7 miRNA, whereas Lin28a-S200A knock-in cells expressed less let-7 miRNA, proliferated faster, and exhibited differentiation defect upon retinoic acid induction. 

Further studies showed that phosphorylation of Lin28a at Ser200 modulated differentiation and proliferation of P19 EC stem cells by decreasing cyclin D1 via let-7 dependent mechanism, and the decreased cyclin D1 decelerated cell proliferation and facilitated the escape from self-renewal cycle to start the differentiation process. 

This study shed new light on how Lin28a function is modulated at the posttranslational level and thereby responds to major signaling pathways. 

The study was supported by the grants from the Ministry of Science and Technology of China and the National Natural Science Foundation of China.

 

Figure: ERK mediated Ser-200 phosphorylation modulated differentiation and proliferation of P19 EC stem cells by decreasing cyclin D1 via let-7 dependent mechanism. (Image by GAO Daming's lab) 

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(Editor: LIU Jia)

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