Skip to content


  • Research highlight
  • Open Access

Cell cycle-independent roles of p19INK4d in human terminal erythropoiesis

Chinese Journal of Cancer201736:22

  • Received: 28 December 2016
  • Accepted: 22 January 2017
  • Published:


  • Thalassemia
  • Cell Cycle Exit
  • Lymphoblast Leukemia Cell
  • Promote Cell Cycle Progression
  • Granulocytic Differentiation

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 phosphatidylethanolamine-binding 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 [810]. 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.


Authors’ contributions

XH wrote the manuscript. JL reviewed and revised the manuscript. Both authors read and approved the final manuscript.


This work was supported in part by the National Natural Science Foundation of China (Grant Nos. 81270576 and 81470362).

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, 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 ( applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

The State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University, Changsha, 410078, Hunan, P. R. China


  1. Li B, Jia N, Kapur R, Chun KT. Cul4a targets p27 for degradation and regulates proliferation, cell cycle exit, and differentiation during erythropoiesis. Blood. 2006;107(11):4291–9.View ArticlePubMedPubMed CentralGoogle Scholar
  2. An X, Schulz VP, Li J, Wu K, Liu J, Xue F, et al. Global transcriptome analyses of human and murine terminal erythroid differentiation. Blood. 2014;123(22):3466–77.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Han X, Zhang J, Peng Y, Peng M, Chen X, Chen H, et al. Unexpected role for p19ink4d in post-transcriptional regulation of gata1 and modulation of human terminal erythropoiesis. Blood. 2017;129(2):226–37.View ArticlePubMedGoogle Scholar
  4. Rao SS, O’Neil J, Liberator CD, Hardwick JS, Dai X, Zhang T, et al. Inhibition of notch signaling by gamma secretase inhibitor engages the rb pathway and elicits cell cycle exit in t-cell acute lymphoblastic leukemia cells. Cancer Res. 2009;69(7):3060–8.View ArticlePubMedGoogle Scholar
  5. Lin S, Wang MJ, Tseng KY. Polypyrimidine tract-binding protein induces p19(ink4d) expression and inhibits the proliferation of h1299 cells. PLoS ONE. 2013;8(3):e58227.View ArticlePubMedPubMed CentralGoogle Scholar
  6. Miller CW, Yeon C, Aslo A, Mendoza S, Aytac U, Koeffler HP. The p19ink4d cyclin dependent kinase inhibitor gene is altered in osteosarcoma. Oncogene. 1997;15(2):231–5.View ArticlePubMedGoogle Scholar
  7. Bai F, Chan HL, Smith MD, Kiyokawa H, Pei XH. P19ink4d is a tumor suppressor and controls pituitary anterior lobe cell proliferation. Mol Cell Biol. 2014;34(12):2121–34.View ArticlePubMedPubMed CentralGoogle Scholar
  8. Hilpert M, Legrand C, Bluteau D, Balayn N, Betems A, Bluteau O, et al. P19ink4d controls hematopoietic stem cells in a cell-autonomous manner during genotoxic stress and through the microenvironment during aging. Stem Cell Rep. 2014;3(6):1085–102.View ArticleGoogle Scholar
  9. Gilles L, Guieze R, Bluteau D, Cordette-Lagarde V, Lacout C, Favier R, et al. P19ink4d links endomitotic arrest and megakaryocyte maturation and is regulated by aml-1. Blood. 2008;111(8):4081–91.View ArticlePubMedGoogle Scholar
  10. Wang Y, Jin W, Jia X, Luo R, Tan Y, Zhu X, et al. Transcriptional repression of cdkn2d by pml/raralpha contributes to the altered proliferation and differentiation block of acute promyelocytic leukemia cells. Cell Death Dis. 2014;5:e1431.View ArticlePubMedPubMed CentralGoogle Scholar


© The Author(s) 2017