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Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-05-1756. This Article Full Text (PDF) All Versions of this Article: 2003-05-1756v1 103/1/120    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fukuda, S. Articles by Pelus, L. M Search for Related Content PubMed PubMed Citation Articles by Fukuda, S. Articles by Pelus, L. M Social Bookmarking                   What's this? Submitted June 2, 2003 Accepted August 28, 2003 Survivin regulates hematopoietic progenitor cell proliferation through p21WAF1/Cip1 dependent and independent pathways Seiji Fukuda, Charlie R Mantel, and Louis M Pelus* Department of Microbiology and Immunology and Walther Oncology Center and the Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN, USA * Corresponding author; email: lpelus{at}iupui.edu. The cyclin dependent kinase inhibitor, p21WAF1/Cip1 and Survivin enhance CFU-GM cell cycle and proliferation and have also been implicated as anti-apoptotic proteins. We investigated the relationships between p21 and Survivin in primary CFU-GM and c-kit+, 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, while p21 gene loss abrogated these effects, indicating a p21 requirement. A dominant-negative form of Survivin as well as p21 gene-deletion accelerated the loss of CFU-GM upon growth factor deprivation, while 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 anti-apoptosis requires p21. In contrast to the p21-dependent anti-apoptotic 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 proliferation of normal hematopoietic cells and that Survivin regulates apoptosis through a p21WAF1/Cip1 dependent pathway but may control S-phase entry independent of p21. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Fukuda, P. Singh, A. Moh, M. Abe, E. M. Conway, H. S. Boswell, S. Yamaguchi, X.-Y. Fu, and L. M. Pelus Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3 Blood, July 9, 2009; 114(2): 394 - 403. [Abstract] [Full Text] [PDF] J. Hoggatt, P. Singh, J. Sampath, and L. M. Pelus Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation Blood, May 28, 2009; 113(22): 5444 - 5455. [Abstract] [Full Text] [PDF] B. Levkau, M. Schafers, J. Wohlschlaeger, K. von Wnuck Lipinski, P. Keul, S. Hermann, N. Kawaguchi, P. Kirchhof, L. Fabritz, J. Stypmann, et al. Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number Circulation, March 25, 2008; 117(12): 1583 - 1593. [Abstract] [Full Text] [PDF] H. Hu, Y. Shikama, I. Matsuoka, and J. Kimura Terminally differentiated neutrophils predominantly express Survivin-2{alpha}, a dominant-negative isoform of Survivin J. Leukoc. Biol., February 1, 2008; 83(2): 393 - 400. [Abstract] [Full Text] [PDF] C. G. Leung, Y. Xu, B. Mularski, H. Liu, S. Gurbuxani, and J. D. Crispino Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells J. Exp. Med., July 9, 2007; 204(7): 1603 - 1611. [Abstract] [Full Text] [PDF] C. Mantel, Y. Guo, M. R. Lee, M.-K. Kim, M.-K. Han, H. Shibayama, S. Fukuda, M. C. Yoder, L. M. Pelus, K.-S. Kim, et al. Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability Blood, May 15, 2007; 109(10): 4518 - 4527. [Abstract] [Full Text] [PDF] E. M. Sloand, L. Pfannes, G. Chen, S. Shah, E. E. Solomou, J. Barrett, and N. S. Young CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins Blood, March 15, 2007; 109(6): 2399 - 2405. [Abstract] [Full Text] [PDF] F. Li and M. G. Brattain Role of the SurvivinGene in Pathophysiology Am. J. Pathol., July 1, 2006; 169(1): 1 - 11. [Abstract] [Full Text] [PDF] S. Fukuda and L. M. Pelus Survivin, a cancer target with an emerging role in normal adult tissues Mol. Cancer Ther., May 1, 2006; 5(5): 1087 - 1098. [Abstract] [Full Text] [PDF] G. J. Wang, X. X. Sui, H. F. Simosa, M. K. Jain, D. C. Altieri, and M. S. Conte Regulation of Vein Graft Hyperplasia by Survivin, an Inhibitor of Apoptosis Protein Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2081 - 2087. [Abstract] [Full Text] [PDF] Z. Wang, J. Sampath, S. Fukuda, and L. M. Pelus Disruption of the Inhibitor of Apoptosis Protein Survivin Sensitizes Bcr-abl-Positive Cells to STI571-Induced Apoptosis Cancer Res., September 15, 2005; 65(18): 8224 - 8232. [Abstract] [Full Text] [PDF] S. Gurbuxani, Y. Xu, G. Keerthivasan, A. Wickrema, and J. D. Crispino Differential requirements for survivin in hematopoietic cell development PNAS, August 9, 2005; 102(32): 11480 - 11485. [Abstract] [Full Text] [PDF] R. Park, C.-C. Chang, Y.-C. Liang, Y. Chung, R. A. Henry, E. Lin, D. E. Mold, and R. C. C. Huang Systemic Treatment with Tetra-O-Methyl Nordihydroguaiaretic Acid Suppresses the Growth of Human Xenograft Tumors Clin. Cancer Res., June 15, 2005; 11(12): 4601 - 4609. [Abstract] [Full Text] [PDF] F. Altznauer, S. Martinelli, S. Yousefi, C. Thurig, I. Schmid, E. M. Conway, M. H. Schoni, P. Vogt, C. Mueller, M. F. Fey, et al. Inflammation-associated Cell Cycle-independent Block of Apoptosis by Survivin in Terminally Differentiated Neutrophils J. Exp. Med., May 17, 2004; 199(10): 1343 - 1354. [Abstract] [Full Text] [PDF]

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