PMID- 20164384
OWN - NLM
STAT- MEDLINE
DCOM- 20100524
LR  - 20211203
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Linking)
VI  - 298
IP  - 5
DP  - 2010 May
TI  - L-Proline induces differentiation of ES cells: a novel role for an amino acid in 
      the regulation of pluripotent cells in culture.
PG  - C982-92
LID - 10.1152/ajpcell.00498.2009 [doi]
AB  - The development of cell therapeutics from embryonic stem (ES) cells will require 
      technologies that direct cell differentiation to specific somatic cell lineages 
      in response to defined factors. The initial step in formation of the somatic 
      lineages from ES cells, differentiation to an intermediate, pluripotent primitive 
      ectoderm-like cell, can be achieved in vitro by formation of early primitive 
      ectoderm-like (EPL) cells in response to a biological activity contained within 
      the conditioned medium MEDII. Fractionation of MEDII has identified two 
      activities required for EPL cell formation, an activity with a molecular mass of 
      <3 kDa and a second, much larger species. Here, we have identified the 
      low-molecular-weight activity as l-proline. An inhibitor of l-proline uptake, 
      glycine, prevented the differentiation of ES cells in response to MEDII. 
      Supplementation of the culture medium of ES cells with >100 M l-proline and some 
      l-proline-containing peptides resulted in changes in colony morphology, cell 
      proliferation, gene expression, and differentiation kinetics consistent with 
      differentiation toward a primitive ectoderm-like cell. This activity appeared to 
      be associated with l-proline since other amino acids and analogs of proline did 
      not exhibit an equivalent activity. Activation of the mammalian target of 
      rapamycin (mTOR) signaling pathway was found to be necessary but not sufficient 
      for l-proline activity; addition of other activators of the mTOR signaling 
      pathway failed to alter the ES cell phenotype. This is the first report 
      describing a role for amino acids in the regulation of pluripotency and cell 
      differentiation and identifies a novel role for the imino acid l-proline.
FAU - Washington, Jennifer M
AU  - Washington JM
AD  - Univ. of Melbourne, Victoria, Australia.
FAU - Rathjen, Joy
AU  - Rathjen J
FAU - Felquer, Fernando
AU  - Felquer F
FAU - Lonic, Ana
AU  - Lonic A
FAU - Bettess, Michael D
AU  - Bettess MD
FAU - Hamra, Nancy
AU  - Hamra N
FAU - Semendric, Ljiljana
AU  - Semendric L
FAU - Tan, Boon Siang Nicholas
AU  - Tan BS
FAU - Lake, Julie-Anne
AU  - Lake JA
FAU - Keough, Rebecca A
AU  - Keough RA
FAU - Morris, Michael B
AU  - Morris MB
FAU - Rathjen, Peter D
AU  - Rathjen PD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100217
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 9DLQ4CIU6V (Proline)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - GMW67QNF9C (Leucine)
RN  - TE7660XO1C (Glycine)
SB  - IM
CIN - Am J Physiol Cell Physiol. 2010 May;298(5):C979-81. PMID: 20219949
MH  - Animals
MH  - Cell Line
MH  - Embryonic Stem Cells/*cytology/*physiology
MH  - Gene Expression Regulation
MH  - Glycine/pharmacology
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics/metabolism
MH  - Leucine/pharmacology
MH  - Mice
MH  - Pluripotent Stem Cells/*cytology/*physiology
MH  - Proline/metabolism/*pharmacology
MH  - Protein Serine-Threonine Kinases/genetics/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
EDAT- 2010/02/19 06:00
MHDA- 2010/05/25 06:00
CRDT- 2010/02/19 06:00
PHST- 2010/02/19 06:00 [entrez]
PHST- 2010/02/19 06:00 [pubmed]
PHST- 2010/05/25 06:00 [medline]
AID - ajpcell.00498.2009 [pii]
AID - 10.1152/ajpcell.00498.2009 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2010 May;298(5):C982-92. doi: 
      10.1152/ajpcell.00498.2009. Epub 2010 Feb 17.