Survivin regulates hematopoietic progenitor cell proliferation through p21WAF1/Cip1-dependent and -independent pathways

Seiji Fukuda, Charlie R. Mantel, Louis M. Pelus

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

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 pro-genitors and that Survivin-mediated anti-apoptosis 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+, Lincells, which was accentuated by p21 deficiency. These results suggest that the Survivin-p21 axis plays an important role in they proliferation of normal hematopoietic cells and that Survivin regulates apoptosis through a p21 WAF/Cip1-dependent pathway but may control S-phase entry independent of p21.

Original languageEnglish (US)
Pages (from-to)120-127
Number of pages8
JournalBlood
Volume103
Issue number1
DOIs
StatePublished - Jan 1 2004

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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