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Blood, 1 January 2004, Vol. 103, No. 1, pp. 120-127.
Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-05-1756.
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HEMATOPOIESIS
Survivin regulates hematopoietic progenitor cell proliferation through p21WAF1/Cip1-dependent and -independent pathways
Seiji Fukuda,
Charlie R. Mantel, and
Louis M. Pelus
From the Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, and the Walther Cancer Institute, Indianapolis, IN.
The cyclin-dependent kinase inhibitor p21WAF1/Cip1 and Survivin enhance granulocyte macrophage colony-forming unit (CFU-GM) cell cycle and proliferation and have been implicated as antiapoptotic proteins. We investigated the relationships between p21 and Survivin in primary CFU-GM and c-kit+, lineage-negative (Lin–) cells and demonstrate p21-dependent and -independent pathways whereby Survivin regulates progenitor cell proliferation. Ectopic Survivin enhanced p21+/+ CFU-GM formation and expansion of c-kit+, Lin– cells, whereas p21 gene loss abrogated these effects, indicating a p21 requirement. A dominant-negative form of Survivin and p21 gene deletion accelerated the loss of CFU-GM upon growth factor deprivation, and wild-type Survivin overexpression inhibited apoptosis of p21+/+ CFU-GM and c-kit+, Lin– cells but not p21–/– cells, suggesting that both Survivin and p21 block apoptosis of progenitors and that Survivin-mediated antiapoptosis requires p21. In contrast to the p21-dependent antiapoptotic effects, Survivin increased the proportion of CFU-GM in S-phase in both p21+/+ and p21–/– cells. Furthermore, modulating Survivin expression increased polyploidy in c-kit+, Lin– cells, which was accentuated by p21 deficiency. These results suggest that the Survivin-p21 axis plays an important role in the proliferation of normal hematopoietic cells and that Survivin regulates apoptosis through a p21 WAF1/Cip1-dependent pathway but may control S-phase entry independent of p21.
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