Cell cycle-independent roles of p19INK4d in human terminal erythropoiesis

© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Normally, cyclin interacts with cyclin-dependent kinase (CDK) to form a cyclin-CDK complex, which promotes cell cycle progression, whereas cyclin-dependent kinase inhibitor (CDKI) molecules inhibit the formation of cyclin-CDK complex, arresting cell cycle. Terminal erythropoiesis is closely coordinated with cell cycle exit, which is regulated by cyclins, CDKs, and CDKIs [1]. In the global transcriptome of human terminal erythropoiesis [2], p19INK4d is expressed highly, and its expression is significantly up-regulated during human terminal erythropoiesis. However, the roles of p19INK4d in terminal erythropoiesis are still unknown. As reported in our article recently published in Blood entitled “Unexpected roles for p19INK4d in posttranscriptional regulation of GATA1 and modulation of human terminal erythropoiesis” [3], we demonstrated what roles p19INK4d plays in human terminal erythropoiesis. We found that, in the erythropoietin-induced, CD34-positive hematopoietic stem cell (HSC) differentiation system, knockdown of p19INK4d delays terminal erythroid differentiation, inhibits erythroblast growth due to increased apoptosis, and leads to the generation of abnormally nucleated late-stage erythroblasts. Unexpectedly, knockdown of p19INK4d did not affect cell cycle, and these functions caused by p19INK4d knockdown were via decreasing levels of GATA-binding protein 1 (GATA1). Furthermore, we found that p19INK4d modulates GATA1 protein levels through a novel pathway, the phosphatidylethanolaminebinding protein 1 (PEBP1)-phosphorylated extracellular signal-regulated kinase (pERK)-heat shock 70 kDa protein (HSP70)-GATA1 pathway [3]. As a classical CDKI member, p19INK4d has been shown to inhibit the formation of cyclin D-CDK4/6 complex, arresting cell cycle in the G0/G1 phase [4]. p19INK4d was often induced to inhibit the proliferation of many kinds of tumor cells, such as T cell acute lymphoblast leukemia cells and lung cancer H1299 cells [4, 5]. Additionally, deletion of p19INK4d leads to the development of many tumors, including osteosarcomas [6] and anterior lobe tumors [7]. p19INK4d is also involved in HSC quiescence, megakaryocyte differentiation, and granulocytic differentiation, which are closely associated with cell cycle arrest [8–10]. However, as shown in our study, p19INK4d played important roles independent of cell cycle regulation, and the lack of cell cycle change was probably due to the compensatory up-regulation of p18INK4c following p19INK4d knockdown. Our findings provide greater understanding of the role that CDKIs play in cell cycle regulation. In conclusion, our study revealed the cell cycle-independent roles of p19INK4d in human terminal erythropoiesis via a novel PEBP1-pERK-HSP70-GATA1 pathway. These findings will likely improve understanding of disordered erythropoiesis, including thalassemia, myelodysplastic syndrome, and congenital dyserythropoietic anemia, and guide future studies that focus on CDKIs.