The SKP2 E3 ligase regulates basal homeostasis and stress-induced regeneration of HSCs

Sonia Rodriguez, Lin Wang, Christen Mumaw, Edward F. Srour, Cristina Lo Celso, Keiichi Nakayama, Nadia Carlesso

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Exit from quiescence and reentry into cell cycle is essential for HSC self-renewal and regeneration. Skp2 is the F-box unit of the SCF E3-ligase that targets the CDK inhibitors (CKIs) p21Cip1, p27Kip1, p57Kip2, and p130 for degradation. These CKIs inhibit the G 1 to S-phase transition of the cell cycle, and their deletion results in increased cell proliferation and decreased stem cell self-renewal. Skp2 deletion leads to CKIs stabilization inducing cell-cycle delay or arrest, and conversely, increased Skp2 expression is often found in cancers. Here, we show that SKP2 expression is increased in HSC and progenitors in response to hematopoietic stress from myelosuppression or after transplantation. At steady state, SKP2 deletion decreased the mitotic activity of HSC and progenitors resulting in enhanced HSC quiescence, increased HSC pool size, and maintenance. However, the inability to rapidly enter cell cycle greatly impaired the short-term repopulating potential of SKP2 null HSC and their ability to regenerate after myeloablative stress. Mechanistically, deletion of SKP2 in HSC and progenitors stabilized CKIs in vivo, particularly p27Kip1, p57Kip2, and p130. Our results demonstrate a previously unrecognized role for SKP2 in regulating HSC and progenitor expansion and hematopoietic regeneration after stress.

Original languageEnglish
Pages (from-to)6509-6519
Number of pages11
JournalBlood
Volume117
Issue number24
DOIs
Publication statusPublished - Jun 16 2011

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Ubiquitin-Protein Ligases
Regeneration
Cell Cycle
Homeostasis
Cells
Reentry
Phase Transition
Cell proliferation
Stem cells
S Phase
Stabilization
Transplantation
Phase transitions
Maintenance
Cell Proliferation
Degradation
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Rodriguez, S., Wang, L., Mumaw, C., Srour, E. F., Lo Celso, C., Nakayama, K., & Carlesso, N. (2011). The SKP2 E3 ligase regulates basal homeostasis and stress-induced regeneration of HSCs. Blood, 117(24), 6509-6519. https://doi.org/10.1182/blood-2010-11-321521

The SKP2 E3 ligase regulates basal homeostasis and stress-induced regeneration of HSCs. / Rodriguez, Sonia; Wang, Lin; Mumaw, Christen; Srour, Edward F.; Lo Celso, Cristina; Nakayama, Keiichi; Carlesso, Nadia.

In: Blood, Vol. 117, No. 24, 16.06.2011, p. 6509-6519.

Research output: Contribution to journalArticle

Rodriguez, S, Wang, L, Mumaw, C, Srour, EF, Lo Celso, C, Nakayama, K & Carlesso, N 2011, 'The SKP2 E3 ligase regulates basal homeostasis and stress-induced regeneration of HSCs', Blood, vol. 117, no. 24, pp. 6509-6519. https://doi.org/10.1182/blood-2010-11-321521
Rodriguez, Sonia ; Wang, Lin ; Mumaw, Christen ; Srour, Edward F. ; Lo Celso, Cristina ; Nakayama, Keiichi ; Carlesso, Nadia. / The SKP2 E3 ligase regulates basal homeostasis and stress-induced regeneration of HSCs. In: Blood. 2011 ; Vol. 117, No. 24. pp. 6509-6519.
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