NKAP Regulates Senescence and Cell Death Pathways in Hematopoietic Progenitors

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.

Identification and characterization of the antigen recognized by the germ cell mAb TRA98 using a human comprehensive wet protein array

“…Using the CWPA, NKAP was successfully identified as the antigen of mAb TRA98, which specifically recognized germ cells. NKAP plays an important role in cell differentiation by affecting gene expression (Pajerowski et al., 2009; Shapiro et al., 2019). These findings may greatly contribute to research into the development and differentiation of germ cells.…”

GRAS1 non-coding RNA protects against DNA damage and cell death by binding and stabilizing NKAP

“…Based on these previous studies, we postulated that GRAS1 lncRNA plays a protective role against cell death in multiple cancer cell types through a common mechanism. NF-κB activating protein (NKAP) is a multifunctional protein which promotes growth and development in highly proliferative human cells (Pajerowski et al 2009, Shapiro et al 2019, Okuda et al 2015. NKAP was first identified in yeast (Chen et al 2003) and has since been characterized as an RNA-binding protein in humans (Burgute et al 2014).…”

“…NF-κB activating protein (NKAP) is a multifunctional protein which promotes growth and development in highly proliferative human cells (Pajerowski et al 2009, Shapiro et al 2019, Okuda et al 2015). NKAP was first identified in yeast (Chen et al 2003) and has since been characterized as an RNA-binding protein in humans (Burgute et al 2014).…”

RNA binding protein NKAP protects glioblastoma cells from ferroptosis by promoting SLC7A11 mRNA splicing in an m6A-dependent manner

“…NKAP functions as an oncogene and participates in the progression of cancer, including gastric cancer [25], colon cancer [26], and renal cell carcinoma [27]. In recent years, research groups from Mayo Clinic and the University of Pennsylvania reported that NKAP played a vital role in immune cell maturation and maintenance [28][29][30][31][32][33]. They found that deletion of NKAP in Treg cells and hematopoietic stem cells leads to cell death [28][29][30].…”

“…In recent years, research groups from Mayo Clinic and the University of Pennsylvania reported that NKAP played a vital role in immune cell maturation and maintenance [28][29][30][31][32][33]. They found that deletion of NKAP in Treg cells and hematopoietic stem cells leads to cell death [28][29][30]. An interesting aspect that attracted us most was that NKAP knockdown induced increased lipid peroxidation in naive T cells [31] and a higher death rate in colon cancer cells [26]; these findings were similar to some of our research results on glioblastoma.…”