JNK1 and 2 play a negative role in reprogramming to pluripotent stem cells by suppressing Klf4 activity

Yao, Ke; Ki, Myoung Ok; Chen, Hanyong; Cho, Yong‐Yeon; Kim, Sung Hyun; Yu, Dong Hoon; Lee, Sung Young; Lee, Kun Yeong; Bae, Ki-Beom; Peng, Cong; Lim, Do Young; Bode, Ann M.; Dong, Zigang

doi:10.1016/j.scr.2013.10.005

Cited by 25 publications

(23 citation statements)

References 45 publications

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“…In liver cancer, c-JUN forms a positive feedback loop with pluripotent genes to expedite cancer stemness [22]. However, the signaling network of c-Jun may be significantly different in MEFs [23]. Moreover, NuRD can interact with pluripotent genes and c-Jun in various ways [13, 24–26], and thus depletion of MBD3 can influence the interaction between c-Jun and pluripotent genes.…”

Section: Discussionmentioning

confidence: 99%

MBD3 inhibits formation of liver cancer stem cells

Han

et al. 2016

Oncotarget

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Liver cancer cells can be reprogrammed into induced cancer stem cells (iCSCs) by exogenous expression of the reprogramming transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM). The nucleosome remodeling and deacetylase (NuRD) complex is essential for reprogramming somatic cells. In this study, we investigated the function of NuRD in the induction of liver CSCs. We showed that suppression of methyl-CpG binding domain protein 3 (MBD3), a core subunit of the NuRD repressor complex, together with OSKM transduction, induces conversion of liver cancer cells into stem-like cells. Expression of the transcription factor c-JUN is increased in MBD3-depleted iCSCs, and c-JUN activates endogenous pluripotent genes and regulates iCSC-related genes. These results indicate that MBD3/NuRD inhibits the induction of iCSCs, while c-JUN facilitates the generation of CSC-like properties. The iCSC reprogramming approach devised here provides a novel platform for dissection of the disordered signaling in liver CSCs. In addition, our results indicate that c-JUN may serve as a potential target for liver cancer therapy.

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Section: Discussionmentioning

confidence: 99%

MBD3 inhibits formation of liver cancer stem cells

Han

et al. 2016

Oncotarget

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“…It is to note that C-Jun amino-terminal kinase (JNK), which is another MAPK pathway enzyme, negatively regulates reprogramming [34]. Thus, we hypothesised that some growth factors present in the serum, such as fibroblast growth factors (FGF), could be barrier to enrichment of high-quality mouse iPS cells [35].…”

Section: Resultsmentioning

confidence: 99%

KSR-Based Medium Improves the Generation of High-Quality Mouse iPS Cells

Liu

Wang

et al. 2014

PLoS ONE

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Induced pluripotent stem (iPS) cells from somatic cells have great potential for regenerative medicine. The efficiency in generation of iPS cells has been significantly improved in recent years. However, the generation of high-quality iPS cells remains of high interest. Consistently, we demonstrate that knockout serum replacement (KSR)-based medium accelerates iPS cell induction and improves the quality of iPS cells, as confirmed by generation of chimeras and all iPS cell-derived offspring with germline transmission competency. Both alkaline phosphatase (AP) activity assay and expression of Nanog have been used to evaluate the efficiency of iPS cell induction and formation of ES/iPS cell colonies; however, appropriate expression of Nanog frequently indicates the quality of ES/iPS cells. Interestingly, whereas foetal bovine serum (FBS)-based media increase iPS cell colony formation, as revealed by AP activity, KSR-based media increase the frequency of iPS cell colony formation with Nanog expression. Furthermore, inhibition of MAPK/ERK by a specific inhibitor, PD0325901, in KSR- but not in FBS-based media significantly increases Nanog-GFP+ iPS cells. In contrast, addition of bFGF in KSR-based media decreases proportion of Nanog-GFP+ iPS cells. Remarkably, PD can rescue Nanog-GFP+ deficiency caused by bFGF. These data suggest that MAPK/ERK pathway influences high quality mouse iPS cells and that KSR- and PD-based media could enrich homogeneous authentic pluripotent stem cells.

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“…50 Recently it was shown that JNK1/2 signaling negatively regulates Klf4 activity. 51 JNK1/2 phosphorylates Klf4 and this inhibits Klf4 transcription and transactivation activity. Also pluripotency factors themselves are involved in the suppression of MAPK signaling.…”

Section: Discussionmentioning

confidence: 99%

Destabilization of pluripotency in the absence of Mad2l2

et al. 2015

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The induction and maintenance of pluripotency requires the expression of several core factors at appropriate levels (Oct4, Sox2, Klf4, Prdm14). A subset of these proteins (Oct4, Sox2, Prdm14) also plays crucial roles for the establishment of primordial germ cells (PGCs). Here we demonstrate that the Mad2l2 (MAD2B, Rev7) gene product is not only required by PGCs, but also by pluripotent embryonic stem cells (ESCs), depending on the growth conditions. Mad2l2¡/¡ ESCs were unstable in LIF/serum medium, and differentiated into primitive endoderm. However, they could be stably propagated using small molecule inhibitors of MAPK signaling. Several components of the MAPK cascade were up-or downregulated even in undifferentiated Mad2l2 ¡/¡ ESCs. Global levels of repressive histone H3 variants were increased in mutant ESCs, and the epigenetic signatures on pluripotency-, primitive endoderm-, and MAPK-related loci differed. Thus, H3K9me2 repressed the Nanog promoter, while the promoter of Gata4 lost H3K27me3 and became de-repressed in LIF/serum condition. Promoters associated with genes involved in MAPK signaling also showed misregulation of these histone marks. Such epigenetic modifications could be indirect consequences of mutating Mad2l2. However, our previous observations suggested the histone methyltransferases as direct (G9a) or indirect (Ezh2) targets of Mad2l2. In effect, the intricate balance necessary for pluripotency becomes perturbed in the absence of Mad2l2.

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JNK1 and 2 play a negative role in reprogramming to pluripotent stem cells by suppressing Klf4 activity

Cited by 25 publications

References 45 publications

MBD3 inhibits formation of liver cancer stem cells

MBD3 inhibits formation of liver cancer stem cells

KSR-Based Medium Improves the Generation of High-Quality Mouse iPS Cells

Destabilization of pluripotency in the absence of Mad2l2

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