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Autophagy and mTORC1 regulate the stochastic phase of somatic cell reprogramming
- Source :
- Nature cell biology. 17(6)
- Publication Year :
- 2014
-
Abstract
- We describe robust induction of autophagy during the reprogramming of mouse fibroblasts to induced pluripotent stem cells by four reprogramming factors (Sox2, Oct4, Klf4 and c-Myc), henceforth 4F. This process occurs independently of p53 activation, and is mediated by the synergistic downregulation of mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy-related genes. The 4F coordinately repress mTORC1, but bifurcate in their regulation of autophagy-related genes, with Klf4 and c-Myc inducing them but Sox2 and Oct4 inhibiting them. On one hand, inhibition of mTORC1 facilitates reprogramming by promoting cell reshaping (mitochondrial remodelling and cell size reduction). On the other hand, mTORC1 paradoxically impairs reprogramming by triggering autophagy. Autophagy does not participate in cell reshaping in reprogramming but instead degrades p62, whose accumulation in autophagy-deficient cells facilitates reprogramming. Our results thus reveal a complex signalling network involving mTORC1 inhibition and autophagy induction in the early phase of reprogramming, whose delicate balance ultimately determines reprogramming efficiency.
- Subjects :
- Somatic cell
Induced Pluripotent Stem Cells
Kruppel-Like Transcription Factors
Down-Regulation
mTORC1
Biology
Mechanistic Target of Rapamycin Complex 1
Autophagy-Related Protein 5
Proto-Oncogene Proteins c-myc
Kruppel-Like Factor 4
Mice
Downregulation and upregulation
SOX2
Autophagy
Animals
RNA, Small Interfering
Induced pluripotent stem cell
Cells, Cultured
Mice, Knockout
SOXB1 Transcription Factors
TOR Serine-Threonine Kinases
Cell Biology
Fibroblasts
Cellular Reprogramming
Class III Phosphatidylinositol 3-Kinases
Cell biology
Mitochondria
KLF4
Multiprotein Complexes
Cancer research
Beclin-1
RNA Interference
biological phenomena, cell phenomena, and immunity
Tumor Suppressor Protein p53
Apoptosis Regulatory Proteins
Reprogramming
Microtubule-Associated Proteins
Octamer Transcription Factor-3
Subjects
Details
- ISSN :
- 14764679
- Volume :
- 17
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Nature cell biology
- Accession number :
- edsair.doi.dedup.....57b4ea3e01cb71b8c7810e6c05fcc7fe