Involvement of casein kinase Iϵ in cytokine-induced granulocytic differentiation

Abstract

Two closely related casein kinase I (CKI) isoforms, CKI␦ and CKI⑀, are ubiquitously expressed in many human tissues, but their specific biologic function remains to be clarified. Here, we provide the first evidence that CKI⑀ is involved in hematopoietic cell differentiation. CKI⑀, but not CKI␦, was down-regulated along with human granulocytic differentiation. The specific down-regulation was observed in granulocyte colony-stimulating factor (G-CSF)-induced cell differentiation of murine interleukin-3 (IL-3)-dependent myeloid progenitor 32D cells. Introduction of wild-type (WT)- IntroductionMembers of the casein kinase I (CKI) family of monomeric serine/threonine kinases are highly conserved from yeast to human and are ubiquitously expressed in different cell types. 1,2 In mammals, 7 isoforms (␣, ␤, ␥1-3, ␦, and ⑀) have been identified. [3][4][5][6] These isoforms share a high degree of similarity within the NH 2 -terminal catalytic domains but show considerable variation in their carboxy-terminal (C-terminal) noncatalytic domains. Their variable C-terminal domains are responsible for substrate specificity and serve to promote differential subcellular localization of individual isoforms and to modulate kinase activity. 4,[7][8][9][10] Studies of CKI homologs in yeast have shown the biologic role of CKI in the regulation of DNA repair and normal cell cycle progression, vesicular trafficking, and cytokinesis. [11][12][13][14][15] The identification of potential substrates for CKI in vitro also possibly inferred that CKI might be involved in a wide variety of cellular functions in mammals. For example, CKI is likely to regulate DNA and RNA metabolism, cellular morphology, vesicular trafficking, DNA damage response and repair, and the activity of various transmembrane receptors. [16][17][18][19][20][21][22][23][24] From the diverse cellular functions of CKI isoforms arose a possibility that CKI is likely to regulate the stability of their substrates, protein turnover, and transport-dependent cellular processes. [25][26][27][28] However, there have been only a few reports in which the phosphorylation by CKI is shown to be essential for the biologic function of the substrates. Unexpectedly, recent genetic analyses in diverse fields have demonstrated that CKI⑀ plays an essential role in regulating several critical in vivo processes such as circadian rhythm, embryogenesis, and morphogenesis in various species. [29][30][31][32] The homolog of CKI␦ and CKI⑀ was first cloned in a screen for a budding yeast mutant, hrr25. 11 Human CKI␦ and CKI⑀ encoded on 2 independent genes localized at chromosome 17q25 and 22q12-13 are basic polypeptides of 49 kDa and 47 kDa, respectively. 4,5 They are the closest isoforms in the CKI family, because their amino acid sequences are 98% identical over their kinase domains and 53% identical over their C-terminal domains. The autophosphorylation of the C-terminal domain has been shown to inhibit its kinase activity. 33 Successful complementation of hrr25 mutants in budding yeast by human CKI␦ ...

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators

“…CSNK1E is a member of the casein kinase I protein family, whose members have been implicated in the control of cytoplasmic and nuclear processes, including DNA replication and repair. The stabilization of components of cytokines and Wnt signaling by CSNK1E might be critical for hematopoietic cell self-renewal (Okamura et al 2004). Interestingly, mutations in a related casein kinase, CSNK1A1, are prevalent in MDS with del(5q), suggesting a role of this gene family in MDS pathogenesis (Schneider et al 2014;Heuser et al 2015).…”

Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia

“…[20][21][22][23][24][25][26]53 To investigate whether Per2 is involved in leukemia, we measured its expression in normal bone marrow and bone marrow from patients with AML. Our results show that Per2 expression is reduced in 42% of AML samples.…”

“…A recent report showed that CKI⑀ is essential for granulocytic differentiation. 53 Perhaps the decreased activity of Per2 in leukemic cells, which are blocked in their terminal differentiation, occurs not only by down-regulation of its mRNA but also by a posttranscriptional mechanism such as phosphorylation.…”

Posttranscriptional Modulation of Cytokine Production in T Cells for the Regulation of Excessive Inflammation by TFL

“…Ba/F3 cells were maintained in RPMI 1640 containing 10% FBS and 15% WEHI-conditioned medium (30). HeLa cells were maintained in DMEM containing 10% calf bovine serum.…”