Inactivation of the polycomb group protein Ring1B unveils an antiproliferative role in hematopoietic cell expansion and cooperation with tumorigenesis associated with Ink4a deletion.
Polycomb group (PcG) proteins act as positive regulators of cell proliferation. Ring1B is a PcG gene essential for embryonic development, but its contribution to cell turnover in regenerating tissues in not known. Here, we have generated a conditional mouse mutant line to study the Ring1B role in adult hematopoiesis. Mutant mice developed a hypocellular bone marrow that paradoxically contained an enlarged, hyperproliferating compartment of immature cells, with an intact differentiation potential. These alterations were associated with differential upregulation of cyclin D2, which occurred in all mutant bone marrow cells, and of p16(Ink4a), observed only in the differentiated compartment. Concurrent inactivation of Ink4a rescued the defective proliferation of maturing cells but did not affect the hyperproliferative activity of progenitors and resulted in a shortening of the onset of lymphomas induced by Ink4a inactivation. These data show that Ring1B restricts the progenitors' proliferation and promotes the proliferation of their maturing progeny by selectively altering the expression pattern of cell cycle regulators along hematopoietic differentiation. The novel antiproliferative role of Ring1B's downregulation of a cell cycle activator may play an important role in the tight control of hematopoietic cell turnover.
Calés
Carmela
C
Developmental and Cell Biology, Centro de Investigaciones Biológicas, Ramiro de Maeztu, 9, 28040 Madrid, Spain.
Román-Trufero
Mónica
M
Pavón
Leticia
L
Serrano
Iván
I
Melgar
Teresa
T
Endoh
Mitsuhiro
M
Pérez
Claudia
C
Koseki
Haruhiko
H
Vidal
Miguel
M
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008223:Lymphoma / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; C489842:Rnf2 protein, mouse; D044767:Ubiquitin-Protein Ligases