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Unexpected role for p19INK4d in post-transcriptional regulation of GATA1 and modulation of human terminal erythropoiesis

Xu Han, Jieying Zhang, Yuanliang Peng, Minyuan Peng, Xiao Chen, Huiyong Chen, Jianhui Song, Xiao Hu, Mao Ye, Jianglin Li, Vijay G. Sankaran, Christopher D. Hillyer, Narla Mohandas, Xiuli An and Jing Liu

Key points

  • Knockdown of cyclin-dependent kinase inhibitor p19INK4d impairs human terminal erythroid differentiation by decreasing GATA1 protein levels.

  • GATA1 protein level is regulated by p19INK4d via PEBP1-pERK-HSP70-GATA1 pathway.

Abstract

Terminal erythroid differentiation is tightly coordinated with cell cycle exit, which is regulated by cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors (CDKI), yet their roles in erythropoiesis remain to be fully defined. We show here that p19INK4d, a member of CDKI family, is abundantly expressed in erythroblasts and that p19INK4d knockdown delayed erythroid differentiation, inhibited cell growth, led to increased apoptosis and generation of abnormally nucleated late stage erythroblasts. Unexpectedly, p19INK4d knockdown did not affect cell cycle. Rather it led to decreased expression of GATA1 protein. Importantly, the differentiation and nuclear defects were rescued by ectopic expression of GATA1. As GATA1 protein is protected by nuclear HSP70, we examined the effects of p19INK4d knockdown on HSP70 and found that p19INK4d knockdown led to decreased expression of HSP70 and its nuclear localization. The reduced levels of HSP70 are the result of reduced ERK activation. Further biochemical analysis revealed that p19INK4d directly binds to Raf kinase inhibitor PEBP1 and that p19INK4d knockdown increased the expression of PEBP1 that in turn led to reduced ERK activation. Thus we have identified an unexpected role for p19INK4d via a novel PEBP1-pERK-HSP70-GATA1 pathway. These findings are likely to have implications for improved understanding of disordered erythropoiesis.

  • Submitted September 12, 2016.
  • Accepted November 14, 2016.