期刊
BLOOD
卷 129, 期 2, 页码 226-237出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-09-739268
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资金
- Natural Science Foundation of China [81270576, 81470362, 81530005, 81170459]
- National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [DK100810, DK26263]
- Science and Technology key project of Hunan Province [2015JC3010]
- postgraduate innovation project of Central South University of China [2015zzts095]
- Mittal students' innovation project of Central South University of China [15MX48]
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 p19 (INK4d,) a member of CDKI family, is abundantly expressed in erythroblasts and that p19 (INK4d) knockdown delayed erythroid differentiation, inhibited cell growth, and led to increased apoptosis and generation of abnormally nucleated late-stage erythroblasts. Unexpectedly, p19 (INK4d) 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. Because the GATA1 protein is protected by nuclear heat shock protein family (HSP) member HSP70, we examined the effects of p19 (INK4d) knockdown on HSP70 and found that p19 (INK4d) knockdown led to decreased expression of HSP70 and its nuclear localization. The reduced levels of HSP70 are the result of reduced extracellular signal-regulated kinase (ERK) activation. Further biochemical analysis revealed that p19 (INK4d) directly binds to Raf kinase inhibitor PEBP1 and that p19 (INK4d) knockdown increased the expression of PEBP1, which in turn led to reduced ERK activation. Thus we have identified an unexpected role for p19 INK4d via a novel PEBP1p- ERK-HSP70-GATA1 pathway. These findings are likely to have implications for improved understanding of disordered erythropoiesis.
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