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Molecular and Cellular Biology, February 2008, p. 1018-1028, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01136-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inactivation of the Polycomb Group Protein Ring1B Unveils an Antiproliferative Role in Hematopoietic Cell Expansion and Cooperation with Tumorigenesis Associated with Ink4a Deletion{triangledown} ,{dagger}

Carmela Calés,2 Mónica Román-Trufero,1 Leticia Pavón,2 Iván Serrano,2 Teresa Melgar,1 Mitsuhiro Endoh,3 Claudia Pérez,4 Haruhiko Koseki,3 and Miguel Vidal1,3*

Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28004 Madrid, Spain,1 Instituto de Investigaciones Biomédicas, Universidad Autónoma de Madrid, Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid, Spain,2 Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan,3 Anatomy and Histopathology, Facultad de Veterinaria, Universidad de León, Campus Vegazana, 24071 León, Spain4

Received 26 June 2007/ Returned for modification 2 August 2007/ Accepted 12 November 2007

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 p16Ink4a, 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.

* Corresponding author. Mailing address: Developmental and Cell Biology, Centro de Investigaciones Biológicas, Ramiro de Maeztu, 9, 28040 Madrid, Spain. Phone: 34 91 837 3112, ext. 4383. Fax: 34 91536 0432. E-mail: mvidal{at}cib.csic.es

{triangledown} Published ahead of print on 26 November 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2008, p. 1018-1028, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01136-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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