PMID- 31729420
OWN - NLM
STAT- MEDLINE
DCOM- 20201106
LR  - 20240210
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Nov 15
TI  - mTORC1 activity is essential for erythropoiesis and B cell lineage commitment.
PG  - 16917
LID - 10.1038/s41598-019-53141-1 [doi]
LID - 16917
AB  - Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that 
      mediates phosphoinositide-3-kinase (PI3K)/AKT signalling. This pathway is 
      involved in a plethora of cellular functions including protein and lipid 
      synthesis, cell migration, cell proliferation and apoptosis. In this study, we 
      proposed to delineate the role of mTORC1 in haemopoietic lineage commitment using 
      knock out (KO) mouse and cell line models. Mx1-cre and Vav-cre expression systems 
      were used to specifically target Raptor(fl/fl) (mTORC1), either in all tissues 
      upon poly(I:C) inoculation, or specifically in haemopoietic stem cells, 
      respectively. Assessment of the role of mTORC1 during the early stages of 
      development in Vav-cre(+)Raptor(fl/fl) mice, revealed that these mice do not 
      survive post birth due to aberrations in erythropoiesis resulting from an arrest 
      in development at the megakaryocyte-erythrocyte progenitor stage. Furthermore, 
      Raptor-deficient mice exhibited a block in B cell lineage commitment. The 
      essential role of Raptor (mTORC1) in erythrocyte and B lineage commitment was 
      confirmed in adult Mx1-cre(+)Raptor(fl/fl) mice upon cre-recombinase induction. 
      These studies were supported by results showing that the expression of key 
      lineage commitment regulators, GATA1, GATA2 and PAX5 were dysregulated in the 
      absence of mTORC1-mediated signals. The regulatory role of mTOR during 
      erythropoiesis was confirmed in vitro by demonstrating a reduction of K562 cell 
      differentiation towards RBCs in the presence of established mTOR inhibitors. 
      While mTORC1 plays a fundamental role in promoting RBC development, we showed 
      that mTORC2 has an opposing role, as Rictor-deficient progenitor cells exhibited 
      an elevation in RBC colony formation ex vivo. Collectively, our data demonstrate 
      a critical role played by mTORC1 in regulating the haemopoietic cell lineage 
      commitment.
FAU - Malik, Natasha
AU  - Malik N
AUID- ORCID: 0000-0002-1768-3544
AD  - Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow, UK.
FAU - Dunn, Karen M
AU  - Dunn KM
AUID- ORCID: 0000-0002-6532-970X
AD  - Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow, UK.
FAU - Cassels, Jennifer
AU  - Cassels J
AD  - Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow, UK.
FAU - Hay, Jodie
AU  - Hay J
AD  - Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow, UK.
FAU - Estell, Christopher
AU  - Estell C
AD  - Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow, UK.
FAU - Sansom, Owen J
AU  - Sansom OJ
AUID- ORCID: 0000-0001-9540-3010
AD  - Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow, UK.
AD  - Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
FAU - Michie, Alison M
AU  - Michie AM
AUID- ORCID: 0000-0002-5404-475X
AD  - Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow, UK. Alison.Michie@glasgow.ac.uk.
LA  - eng
GR  - 21139/CRUK_/Cancer Research UK/United Kingdom
GR  - MR/K014854/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191115
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Biomarkers)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - B-Lymphocytes/*cytology/*metabolism
MH  - Biomarkers
MH  - *Cell Differentiation
MH  - Cell Line, Tumor
MH  - Cell Lineage
MH  - *Erythropoiesis
MH  - Humans
MH  - *Lymphopoiesis
MH  - Mechanistic Target of Rapamycin Complex 1/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Models, Biological
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
PMC - PMC6858379
COIS- The authors declare no competing interests.
EDAT- 2019/11/16 06:00
MHDA- 2020/11/11 06:00
PMCR- 2019/11/15
CRDT- 2019/11/16 06:00
PHST- 2019/05/13 00:00 [received]
PHST- 2019/10/26 00:00 [accepted]
PHST- 2019/11/16 06:00 [entrez]
PHST- 2019/11/16 06:00 [pubmed]
PHST- 2020/11/11 06:00 [medline]
PHST- 2019/11/15 00:00 [pmc-release]
AID - 10.1038/s41598-019-53141-1 [pii]
AID - 53141 [pii]
AID - 10.1038/s41598-019-53141-1 [doi]
PST - epublish
SO  - Sci Rep. 2019 Nov 15;9(1):16917. doi: 10.1038/s41598-019-53141-1.