Lineage-specific regulation of cell cycle control gene expression during haematopoietic cell differentiation.
To maintain the fidelity and integrity of blood formation, the cell cycle is under strict regulation during haematopoietic cell differentiation. To elucidate the molecular mechanisms of cell cycle regulation during haematopoiesis, we examined cell cycle control gene expression during lineage-specific differentiation from CD34+ progenitor cells. Expression of cyclin-dependent kinases (cdks) and cyclins, except cdk4, was generally suppressed in CD34+ cells freshly isolated from the bone marrow of healthy volunteers. Among four major cdk inhibitors, p16 was expressed more highly in CD34+ cells than in CD34-negative bone marrow mononuclear cells, whereas the amounts of p21 and p27 transcripts increased in the CD34- population. The behaviour of cell cycle control genes during haematopoietic differentiation was classified into four patterns: (i) universal upregulation (cdc2, cdk2, cyclin A, cyclin B and p21); (ii) upregulation in specific lineages (cyclin D1, cyclin D3 and p15); (iii) no induction or stable expression (cdk4, cyclin D2, cyclin E and p27); and (iv) universal downregulation (p16). Lineage-specific changes included the sustained elevation of cdc2 and cyclin A during erythroid differentiation, cyclin D1 and p15 induction in myeloid lineage and selective upregulation of cyclin D3 in megakaryocytes. Blocking induction of cyclin D3 resulted in the inhibition of megakaryocytic differentiation. These results suggest that the expression of cell cycle control genes is distinctively regulated in a lineage-dependent manner, reflecting the cell cycle characteristics of each lineage. Some of these genes play an essential role in the process of differentiation itself.
Furukawa
Y
Y
Division of Molecular Haematopoiesis, Centre for Molecular Medicine, and Department of Haematology, Jichi Medical School, Tochigi, Japan. furuyu@jichi.ac.jp
Kikuchi
J
J
Nakamura
M
M
Iwase
S
S
Yamada
H
H
Matsuda
M
M
D018952:Antigens, CD34; D015415:Biomarkers / Q000032:analysis; D016203:CDC2 Protein Kinase / Q000235:genetics; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D019925:Cyclin A / Q000235:genetics; D019926:Cyclin B / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D016213:Cyclins / Q000235:genetics; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D018816:Genes, cdc; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins
D018952:Antigens, CD34; D015415:Biomarkers; C080336:CCND2 protein, human; C534696:CCND3 protein, human; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases