Akt signaling regulates side population cell phenotype via Bcrp1 translocation.
Akt is an important regulator of cell survival, growth, and glucose metabolism in many cell types, but the role of this signaling molecule in hematopoietic stem cells is poorly defined. Side population (SP) cells are enriched for hematopoietic stem cell activity and are defined by their ability to efficiently efflux Hoechst 33342. Bone marrow from Akt1-null mice exhibited a reduced SP fraction. However, bone marrow cellularity, growth factor-responsive progenitor cultures, and engraftable stem cells were normal in these mice. Treatment of bone marrow with LY294002, an inhibitor of the Akt effector protein phosphatidylinositol 3-kinase, led to a reversible loss of the SP fraction. Bcrp1, which encodes the Hoechst dye transporter, was translocated from the membrane to the intracellular compartment under conditions that promote the SP-depleted state. Lentivirus-mediated overexpression of Akt1 in bone marrow markedly increased the SP fraction, whereas there was no effect on bone marrow from Bcrp(-/-) mice. These data suggest that Akt signaling modulates the SP cell phenotype by regulating the expression of Bcrp1.
Mogi
Masaki
M
Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Yang
Jiang
J
Lambert
Jean-Francois
JF
Colvin
Gerald A
GA
Shiojima
Ichiro
I
Skurk
Carsten
C
Summer
Ross
R
Fine
Alan
A
Quesenberry
Peter J
PJ
Walsh
Kenneth
K
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001562:Benzimidazoles / Q000494:pharmacology; D019921:Biotinylation; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007763:Lac Operon; D016086:Lentivirus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013234:Stem Cells; D013347:Subcellular Fractions
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001562:Benzimidazoles; D002867:Chromones; D004791:Enzyme Inhibitors; D006133:Growth Substances; D009025:Morpholines; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C116614:ABCG2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C017807:bisbenzimide ethoxide trihydrochloride