APC/C Regulates the Balance Between Maintenance and Differentiation of Hematopoietic Stem and Progenitor Cells

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2018 Oct 26

PMID 30357422

Citations 3

Authors

Daniel Ewerth

Stefanie Kreutmair

Andrea Schmidts

Gabriele Ihorst

Marie Follo

Dagmar Wider

Julia Felthaus

Julia Schuler

Justus Duyster

Anna Lena Illert

Monika Engelhardt

Ralph Wasch

Affiliations

Soon will be listed here.

Abstract

Hematopoietic stem and progenitor cells (HSPCs) represent the lifelong source of all blood cells and continuously regenerate the hematopoietic system through differentiation and self-renewal. The process of differentiation is initiated in the G phase of the cell cycle, when stem cells leave their quiescent state. During G, the anaphase-promoting complex or cyclosome associated with the coactivator Cdh1 is highly active and marks proteins for proteasomal degradation to regulate cell proliferation. Following Cdh1 knockdown in HSPCs, we analyzed human and mouse hematopoiesis in vitro and in vivo in competitive transplantation assays. We found that Cdh1 is highly expressed in human CD34 HSPCs and downregulated in differentiated subsets; whereas, loss of Cdh1 restricts myeloid differentiation, supports B cell development and preserves immature short-term HSPCs without affecting proliferation or viability. Our data highlight a role of Cdh1 as a regulator of balancing the maintenance of HSPCs and differentiation into mature blood cells.

Citing Articles

The Role of the APC/C and Its Coactivators Cdh1 and Cdc20 in Cancer Development and Therapy.

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Insufficiency of FZR1 disturbs HSC quiescence by inhibiting ubiquitin-dependent degradation of RUNX1 in aplastic anemia.

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References

Gieffers C, PETERS B, Kramer E, Dotti C, Peters J . Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons. Proc Natl Acad Sci U S A. 1999; 96(20):11317-22. PMC: 18031. DOI: 10.1073/pnas.96.20.11317. View

Sorensen C, Lukas C, Kramer E, Peters J, Bartek J, Lukas J . Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis. Mol Cell Biol. 2000; 20(20):7613-23. PMC: 86321. DOI: 10.1128/MCB.20.20.7613-7623.2000. View

Stroschein S, Bonni S, Wrana J, Luo K . Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN. Genes Dev. 2001; 15(21):2822-36. PMC: 312804. DOI: 10.1101/gad.912901. View

Wan Y, Liu X, Kirschner M . The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. Mol Cell. 2001; 8(5):1027-39. DOI: 10.1016/s1097-2765(01)00382-3. View

Wasch R, Cross F . APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit. Nature. 2002; 418(6897):556-62. DOI: 10.1038/nature00856. View

Konishi Y, Stegmuller J, Matsuda T, Bonni S, Bonni A . Cdh1-APC controls axonal growth and patterning in the mammalian brain. Science. 2004; 303(5660):1026-30. DOI: 10.1126/science.1093712. View

Bashir T, Dorrello N, Amador V, Guardavaccaro D, Pagano M . Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature. 2004; 428(6979):190-3. DOI: 10.1038/nature02330. View

Wei W, Ayad N, Wan Y, Zhang G, Kirschner M, Kaelin Jr W . Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature. 2004; 428(6979):194-8. DOI: 10.1038/nature02381. View

Wasch R, Engelbert D . Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Oncogene. 2005; 24(1):1-10. DOI: 10.1038/sj.onc.1208017. View

10.

Benmaamar R, Pagano M . Involvement of the SCF complex in the control of Cdh1 degradation in S-phase. Cell Cycle. 2005; 4(9):1230-2. DOI: 10.4161/cc.4.9.2048. View

11.

Stegmuller J, Konishi Y, Huynh M, Yuan Z, DiBacco S, Bonni A . Cell-intrinsic regulation of axonal morphogenesis by the Cdh1-APC target SnoN. Neuron. 2006; 50(3):389-400. DOI: 10.1016/j.neuron.2006.03.034. View

12.

Lasorella A, Stegmuller J, Guardavaccaro D, Liu G, Carro M, Rothschild G . Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature. 2006; 442(7101):471-4. DOI: 10.1038/nature04895. View

13.

Peters J . The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol. 2006; 7(9):644-56. DOI: 10.1038/nrm1988. View

14.

Binne U, Classon M, Dick F, Wei W, Rape M, Kaelin Jr W . Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol. 2006; 9(2):225-32. DOI: 10.1038/ncb1532. View

15.

Wu G, Glickstein S, Liu W, Fujita T, Li W, Yang Q . The anaphase-promoting complex coordinates initiation of lens differentiation. Mol Biol Cell. 2007; 18(3):1018-29. PMC: 1805114. DOI: 10.1091/mbc.e06-09-0809. View

16.

Liu W, Wu G, Li W, Lobur D, Wan Y . Cdh1-anaphase-promoting complex targets Skp2 for destruction in transforming growth factor beta-induced growth inhibition. Mol Cell Biol. 2007; 27(8):2967-79. PMC: 1899917. DOI: 10.1128/MCB.01830-06. View

17.

Li W, Wu G, Wan Y . The dual effects of Cdh1/APC in myogenesis. FASEB J. 2007; 21(13):3606-17. DOI: 10.1096/fj.07-8159com. View

18.

Engelbert D, Schnerch D, Baumgarten A, Wasch R . The ubiquitin ligase APC(Cdh1) is required to maintain genome integrity in primary human cells. Oncogene. 2007; 27(7):907-17. DOI: 10.1038/sj.onc.1210703. View

19.

Orford K, Scadden D . Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet. 2008; 9(2):115-28. DOI: 10.1038/nrg2269. View

20.

Fujita T, Liu W, Doihara H, Date H, Wan Y . Dissection of the APCCdh1-Skp2 cascade in breast cancer. Clin Cancer Res. 2008; 14(7):1966-75. DOI: 10.1158/1078-0432.CCR-07-1585. View