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Molecular and Cellular Biology, January 2003, p. 389-401, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.389-401.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Control of the Replicative Life Span of Human Fibroblasts by p16 and the Polycomb Protein Bmi-1

Koji Itahana,1,{dagger} Ying Zou,1 Yoko Itahana,2 Jose-Luis Martinez,3 Christian Beausejour,1 Jacqueline J. L. Jacobs,4 Maarten van Lohuizen,4 Vimla Band,3 Judith Campisi,1 and Goberdhan P. Dimri3*

Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720,1 California Pacific Medical Center, San Francisco, California 94115,2 Division of Radiation and Cancer Biology, Department of Radiation Oncology, New England Medical Center, Boston, Massachusetts 02111,3 Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands4

Received 20 August 2002/ Returned for modification 20 September 2002/ Accepted 30 September 2002

The polycomb protein Bmi-1 represses the INK4a locus, which encodes the tumor suppressors p16 and p14ARF. Here we report that Bmi-1 is downregulated when WI-38 human fibroblasts undergo replicative senescence, but not quiescence, and extends replicative life span when overexpressed. Life span extension by Bmi-1 required the pRb, but not p53, tumor suppressor protein. Deletion analysis showed that the RING finger and helix-turn-helix domains of Bmi-1 were required for life span extension and suppression of p16. Furthermore, a RING finger deletion mutant exhibited dominant negative activity, inducing p16 and premature senescence. Interestingly, presenescent cultures of some, but not all, human fibroblasts contained growth-arrested cells expressing high levels of p16 and apparently arrested by a p53- and telomere-independent mechanism. Bmi-1 selectively extended the life span of these cultures. Low O2 concentrations had no effect on p16 levels or life span extension by Bmi-1 but reduced expression of the p53 target, p21. We propose that some human fibroblast strains are more sensitive to stress-induced senescence and have both p16-dependent and p53/telomere-dependent pathways of senescence. Our data suggest that Bmi-1 extends the replicative life span of human fibroblasts by suppressing the p16-dependent senescence pathway.

* Corresponding author. Mailing address: Department of Radiation Oncology, New England Medical Center, 750 Washington St., NEMC #824, Boston, MA 02111. Phone: (617) 636-9002. Fax: (617) 636-6205. E-mail: GDimri{at}Lifespan.org.

{dagger} Present address: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.

Molecular and Cellular Biology, January 2003, p. 389-401, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.389-401.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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