NKAP Regulates Senescence and Cell Death Pathways in Hematopoietic Progenitors

Michael Jeremy Shapiro, Joshua Anderson, Michael Jonathan Lehrke, Meibo Chen, Molly Nelson Holte, Virginia Smith Shapiro

Research output: Contribution to journalArticle

Abstract

NKAP is a multi-functional nuclear protein that has been shown to be essential for hematopoiesis. Deletion of NKAP in hematopoietic stem cells (HSCs) was previously found to result in rapid lethality and hematopoietic failure. NKAP deficient cells also exhibited diminished proliferation and increased expression of the cyclin dependent kinase inhibitors (CDKIs) p19 Ink4d and p21 Cip1. To determine how dysregulation of CDKI expression contributes to the effects of NKAP deficiency, NKAP was deleted in mice also deficient in p19 Ink4d or p21 Cip1 using poly-IC treatment to induce Mx1-cre. Hematopoietic failure and lethality were not prevented by deficiency in either CDKI when NKAP was deleted. Inducible deletion of NKAP in cultured hematopoietic progenitors ex vivo resulted in a senescent phenotype and altered expression of numerous cell cycle regulators including the CDKI p16 INK4a. Interestingly, while combined deficiency in p16 INK4a and p21 Cip1 did not reverse the effect of NKAP deficiency on hematopoiesis in vivo, it did shift the consequence of NKAP deficiency from senescence to apoptosis in ex vivo cultures. These results suggest that NKAP may limit cellular stress that can trigger cell cycle withdrawal or cell death, a role critical for the maintenance of a viable pool of hematopoietic progenitors.

Original languageEnglish (US)
Article number214
JournalFrontiers in Cell and Developmental Biology
Volume7
DOIs
StatePublished - Oct 2 2019

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Cyclin-Dependent Kinases
Hematopoiesis
Cyclin-Dependent Kinase Inhibitor p19
Cell Cycle
Cell Death
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p21
Nuclear Proteins
Hematopoietic Stem Cells
Maintenance
Apoptosis
Phenotype

Keywords

  • apoptosis
  • cyclin dependent kinase inhibitor
  • hematopoiesis
  • NKAP
  • senescence

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

Cite this

NKAP Regulates Senescence and Cell Death Pathways in Hematopoietic Progenitors. / Shapiro, Michael Jeremy; Anderson, Joshua; Lehrke, Michael Jonathan; Chen, Meibo; Nelson Holte, Molly; Shapiro, Virginia Smith.

In: Frontiers in Cell and Developmental Biology, Vol. 7, 214, 02.10.2019.

Research output: Contribution to journalArticle

Shapiro, Michael Jeremy ; Anderson, Joshua ; Lehrke, Michael Jonathan ; Chen, Meibo ; Nelson Holte, Molly ; Shapiro, Virginia Smith. / NKAP Regulates Senescence and Cell Death Pathways in Hematopoietic Progenitors. In: Frontiers in Cell and Developmental Biology. 2019 ; Vol. 7.
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