miR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53.
The role of miRNAs in regulating megakaryocyte differentiation was examined using bipotent K562 human leukemia cells. miR-34a is strongly up-regulated during phorbol ester-induced megakaryocyte differentiation, but not during hemin-induced erythrocyte differentiation. Enforced expression of miR-34a in K562 cells inhibits cell proliferation, induces cell-cycle arrest in G(1) phase, and promotes megakaryocyte differentiation as measured by CD41 induction. miR-34a expression is also up-regulated during thrombopoietin-induced differentiation of CD34(+) hematopoietic precursors, and its enforced expression in these cells significantly increases the number of megakaryocyte colonies. miR-34a directly regulates expression of MYB, facilitating megakaryocyte differentiation, and of CDK4 and CDK6, to inhibit the G(1)/S transition. However, these miR-34a target genes are down-regulated rapidly after inducing megakaryocyte differentiation before miR-34a is induced. This suggests that miR-34a is not responsible for the initial down-regulation but may contribute to maintaining their suppression later on. Previous studies have implicated miR-34a as a tumor suppressor gene whose transcription is activated by p53. However, in p53-null K562 cells, phorbol esters induce miR-34a expression independently of p53 by activating an alternative phorbol ester-responsive promoter to produce a longer pri-miR-34a transcript.
Navarro
Francisco
F
Immune Disease Institute and Department of Pediatrics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Gutman
David
D
Meire
Eti
E
Cáceres
Mario
M
Rigoutsos
Isidore
I
Bentwich
Zvi
Z
Lieberman
Judy
J
D018952:Antigens, CD34; D002273:Carcinogens / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D010703:Phorbol Esters / Q000494:pharmacology; D040201:Platelet Membrane Glycoprotein IIb / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000502:physiology; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D013926:Thrombopoietin / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D018952:Antigens, CD34; D002273:Carcinogens; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D010703:Phorbol Esters; D040201:Platelet Membrane Glycoprotein IIb; D020598:Proto-Oncogene Proteins c-myb; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013926:Thrombopoietin