title: Forced expression of p21 in GPIIb-p21 transgenic mice induces abnormalities in the proliferation of erythroid and megakaryocyte progenitors and primitive hematopoietic cells.
abstract: OBJECTIVE
  p21(WAF1/Cip/kip) and p27(Kip1) are cyclin-dependant kinase inhibitors controlling cell-cycle exit and differentiation of numerous cell types. Among hematopoietic cells, megakaryocytes express high levels of p21, while in erythroid cells, p27(Kip1) is predominant. As p21 and p27 could display overlapping functions and as megakaryocytes and erythroid cells derive from a bipotent progenitor, we developed an in vivo model to determine the specific role of p21 in controlling the proliferation/differentiation balance of erythroid and megakaryocytic progenitors.
  
  
  METHODS
  Transgenic mice that overexpressed p21 under the control of the human GPIIb promoter in early progenitors and along megakaryocytic differentiation were generated. Different subsets of hematopoietic progenitors (BFU and CFU) and primitive cells (CAFC, LTC-IC) were analyzed by methylcellulose assay. Phenotypic evolution and clonogenic properties of the lin(-) population were analyzed along erythroid and megakaryocytic differentiation.
  
  
  RESULTS
  We observed p21 ectopic expression in early hematopoietic progenitors (lin(-)Sca(+)), megakaryocytes, and, to a lesser extent, erythroid cells. This expression induced an important decrease in the number of CFU-MK, BFU-E, CFU-E, primitive progenitors (CAFC day 35), and LTC-IC, but did not affect the maturation process of these cells and the blood cell count.
  
  
  CONCLUSIONS
  We show that variation of p21 expression level changes the fate of hematopoietic cells by favoring either proliferation or differentiation pathways. This effect of p21 is exerted not only at the level of primitive progenitors but also in more mature progenitors. However, in vivo, a systemic compensation mechanism is most likely activated in response to variations of the flow of progenitor production.
authors.affiliation: INSERM, Unité 506, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Albanese
authors.forename: Jalila
authors.initials: J
authors.lastname: Chagraoui
authors.forename: Martine
authors.initials: M
authors.lastname: Charon
authors.forename: Laurence
authors.initials: L
authors.lastname: Cocault
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dusanter-Fourt
authors.forename: Paul Henri
authors.initials: PH
authors.lastname: Romeo
authors.forename: Georges
authors.initials: G
authors.lastname: Uzan
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D005813:Genes, Synthetic; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000502:physiology
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018076:DNA, Complementary; D040201:Platelet Membrane Glycoprotein IIb; D011993:Recombinant Fusion Proteins