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Regulation of c-Myc Expression by Ahnak Promotes Induced Pluripotent Stem Cell Generation

Title
Regulation of c-Myc Expression by Ahnak Promotes Induced Pluripotent Stem Cell Generation
Author
박장환
Keywords
KRUPPEL-LIKE FACTORS; HUMAN SOMATIC-CELLS; PROTEIN-KINASE-C; TRANSCRIPTION FACTOR; IPSC GENERATION; FIBROBLASTS; MOUSE; INHIBITION; ACTIVATION; EFFICIENCY
Issue Date
2016-01
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v. 291, NO 2, Page. 752-761
Abstract
We have previously reported that Ahnak-mediated TGF beta signaling leads to down-regulation of c-Myc expression. Here, we show that inhibition of Ahnak can promote generation of induced pluripotent stem cells (iPSC) via up-regulation of endogenous c-Myc. Consistent with the c-Myc inhibitory role of Ahnak, mouse embryonic fibroblasts from Ahnak-deficient mouse (Ahnak(-/-) MEF) show an increased level of c-Myc expression compared with wild type MEF. Generation of iPSC with just three of the four Yamanaka factors, Oct4, Sox2, and Klf4 (hereafter 3F), was significantly enhanced in Ahnak(-/-) MEF. Similar results were obtained when Ahnak-specific shRNA was applied to wild type MEF. Of note, expression of Ahnak was significantly induced during the formation of embryoid bodies from embryonic stem cells, suggesting that Ahnak-mediated c-Myc inhibition is involved in embryoid body formation and the initial differentiation of pluripotent stem cells. The iPSC from 3F-infected Ahnak(-/-) MEF cells (Ahnak(-/-) - iPSC-3F) showed expression of all stem cell markers examined and the capability to form three primary germ layers. Moreover, injection of Ahnak(-/-) - iPSC-3F into athymic nude mice led to development of teratoma containing tissues from all three primary germ layers, indicating that iPSC from Ahnak(-/-) MEF are bona fide pluripotent stem cells. Taken together, these data provide evidence for a new role for Ahnak in cell fate determination during development and suggest that manipulation of Ahnak and the associated signaling pathway may provide a means to regulate iPSC generation.
URI
http://www.jbc.org/content/291/2/752http://hdl.handle.net/20.500.11754/30589
ISSN
0021-9258; 1083-351X
DOI
10.1074/jbc.M115.659276
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COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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