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Phosphorylation of serine 21 modulates the proliferation inhibitory more than the differentiation inducing effects of C/EBP? in K562 cells.

ABSTRACT: The CCAAT/enhancer binding protein ? (C/EBP?) is a transcription factor required for differentiation of myeloid progenitors. In acute myeloid leukemia (AML) cells expressing the constitutively active FLT3-ITD receptor tyrosine kinase, MAP kinase-dependent phosphorylation of serine 21 (S21) inhibits the ability of C/EBP? to induce granulocytic differentiation. To assess whether this post-translational modification also modulates the activity of C/EBP? in BCR/ABL-expressing cells, we tested the biological effects of wild-type and mutant C/EBP? mimicking phosphorylated or non-phosphorylatable serine 21 (S21D and S21A, respectively) in K562 cells ectopically expressing tamoxifen-regulated C/EBP?-ER chimeric proteins. We show here that S21D C/EBP?-ER induced terminal granulocytic differentiation of K562 cells almost as well as wild-type C/EBP?-ER, while S21A C/EBP?-ER was less efficient. Furthermore, wild-type C/EBP? suppressed the proliferation and colony formation of K562 cells vigorously, while S21D and S21A C/EBP? mutants had more modest anti-proliferative effects. Both mutants were less effective than wild-type C/EBP? in suppressing endogenous E2F-dependent transactivation and bound less E2F-2 and/or E2F-3 proteins in anti-C/EBP? immunoprecipitates. Together, these findings suggest that mutation of S21 more than its phosphorylation inhibits the anti-proliferative effects of C/EBP? due to reduced interaction with or impaired regulation of the activity of E2F proteins. By contrast, phosphorylation of serine 21 appears to have a modest role in modulating the differentiation-inducing effects of C/EBP? in K562 cells.

SUBMITTER: Fragliasso V

PROVIDER: S-EPMC3329570 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Phosphorylation of serine 21 modulates the proliferation inhibitory more than the differentiation inducing effects of C/EBPα in K562 cells.

Fragliasso Valentina V Chiodo Yuri Y Ferrari-Amorotti Giovanna G Soliera Angela Rachele AR Manzotti Gloria G Cattelani Sara S Candini Olivia O Grisendi Giulia G Vergalli Jenny J Mariani Samanta Antonella SA Guerzoni Clara C Calabretta Bruno B

Journal of cellular biochemistry 20120501 5

The CCAAT/enhancer binding protein α (C/EBPα) is a transcription factor required for differentiation of myeloid progenitors. In acute myeloid leukemia (AML) cells expressing the constitutively active FLT3-ITD receptor tyrosine kinase, MAP kinase-dependent phosphorylation of serine 21 (S21) inhibits the ability of C/EBPα to induce granulocytic differentiation. To assess whether this post-translational modification also modulates the activity of C/EBPα in BCR/ABL-expressing cells, we tested the bi ...[more]

PMID: 22212957

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Project description:Macrophages are key immune cells for the initiation and development of atherosclerotic lesions. However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors that play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust antiatherosclerotic transcriptional program in macrophages that can be affected by LXRα S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDL receptor (LDLR)-deficient atherosclerotic background (M-S196ALdlr-KO). M-S196ALdlr-KO mice fed a high-fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXRα-S196A during atherosclerosis development. Remarkably, expression of several proliferation-promoting factors, including the protooncogene FoxM1 and its targets, is induced by LXRα-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196ALdlr-KO mice. Moreover, disrupted LXRα phosphorylation increases expression of phagocytic molecules, resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXRα-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this posttranslational modification. Overall, our findings demonstrate that LXRα phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.

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Phosphorylation of serine 21 modulates the proliferation inhibitory more than the differentiation inducing effects of C/EBP? in K562 cells.

Publications

Phosphorylation of serine 21 modulates the proliferation inhibitory more than the differentiation inducing effects of C/EBPα in K562 cells.

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