Page 55 - Haematologica3

miR-451 inhibits Cab39 for stress erythropoiesis
while numerous studies, including the current one, reveal a positive effect of mTOR on erythropoiesis, other studies show that mTOR inhibition may have beneficial effects in some forms of anemia including SCD and thalassemia,46,47 again emphasizing context- or disease-dependent func- tions for this pathway. Our mouse model makes it possi- ble to investigate further the roles of miR-144/451, includ- ing its effects on mTOR, in physiological adaptations to various red cell disorders.
miR-144/451 is a bicistronic gene whose expression is directly controlled by GATA1 in erythroid cells.10,15 Interestingly, our research and that of others had previous- ly observed that: 1) miR-144 level is always lower than miR-451 level in both fetal and adult erythroid cells;10,14 and 2) the expression of miR-144 is ubiquitous whereas the expression of miR-451 is much more constrained in hematopoietic compartments during embryonic develop- ment.48,49 These data suggest that overlapping and inde- pendent mechanisms regulate the differential expression of miR-144 and miR-451. The current study focuses on an miR-451-dependent mechanism for regulating stress ery- thropoiesis. However, it is not clear whether miR-144 impacts this process. Of note, suppression of miR-144
inhibits erythropoiesis in cultured human CD34+ cells.50 In future studies, it will be interesting to investigate the effects of miR-144 and miR-451 on erythropoiesis separate- ly by examining mice that harbor single miR-specific mutations.
Acknowledgments
The authors would like to thank Keith Laycock (St. Jude Children's Research Hospital) and Yuanjun Yu for language editing.
Funding
This work is supported by the National Natural Science Foundation of China (grant n. 81470277 to DY), a grant from the Ministry of Finance of China for the “Biology & Medical Science Innovation Team” program (to DY), and the Priority Academic Program Development of Jiangsu Higher Education Institution (Veterinary Medicine) (to DY) and R01 DK092318 (to MW). XF is also supported by the National Natural Science Foundation of China (grant n. 81402484), the Jiangsu Provincial Natural Science Foundation (grant n. BK20140497) and Natural Science Fund for Colleges and Universities in Jiangsu Province (grant n. 14KJB310024).
References
1. Hosokawa K, Muranski P, Feng X, et al. Identification of novel microRNA signa- tures linked to acquired aplastic anemia. Haematologica. 2015;100(12):1534-1545.
2. Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012;148(6):1172-1187.
3. Hattangadi SM, Wong P, Zhang L, Flygare J, Lodish HF. From stem cell to red cell: regu- lation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood. 2011;118(24):6258- 6268.
4. Huang X, Gschweng E, Van Handel B, Cheng D, Mikkola HK, Witte ON. Regulated expression of microRNAs- 126/126* inhibits erythropoiesis from human embryonic stem cells. Blood. 2011; 117(7):2157-2165.
5. Wang F, Zhu Y, Guo L, et al. A regulatory cir- cuit comprising GATA1/2 switch and microRNA-27a/24 promotes erythropoiesis. Nucleic Acids Res. 2014;42(1):442-457.
6. Zhai PF, Wang F, Su R, et al. The regulatory roles of microRNA-146b-5p and its target platelet-derived growth factor receptor α (PDGFRA) in erythropoiesis and megakaryocytopoiesis. J Biol Chem. 2014; 289(33):22600-22613.
7. Fu YF, Du TT, Dong M, et al. Mir-144 selec- tively regulates embryonic α-hemoglobin synthesis during primitive erythropoiesis. Blood. 2008;113(6):1340-1349.
8. Pase L, Layton JE, Kloosterman WP, Carradice D, Waterhouse PM, Lieschke GJ. miR-451 regulates zebrafish erythroid mat- uration in vivo via its target gata2. Blood. 2009;113(8):1794-1804.
9. Zhan M, Miller CP, Papayannopoulou T, Stamatoyannopoulos G, Song CZ. MicroRNA expression dynamics during murine and human erythroid differentia- tion. Exp Hematol. 2007;35(7):1015-1025.
A GATA-1-regulated microRNA locus essential for erythropoiesis. Proc Natl Acad Sci USA. 2008;105(9):3333-3338.
11. Zhang L, Flygare J, Wong P, Lim B, Lodish HF. miR-191 regulates mouse erythroblast enucleation by down-regulating Riok3 and Mxi1. Genes Dev. 2011;25(2):119-124.
12. Yang JS, Maurin T, Robine N, et al. Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2- mediated microRNA biogenesis. Proc Natl Acad Sci USA. 2010;107(34):15163-15168.
13. Patrick DM, Zhang CC, Tao Y, et al. Defective erythroid differentiation in miR- 451 mutant mice mediated by 14-3-3zeta. Genes Dev. 2010;24(15):1614-1619.
14. Rasmussen KD, Simmini S, Abreu- Goodger C, et al. The miR-144/451 locus is required for erythroid homeostasis. J Exp Med. 2010;207(7):1351-1358.
15. Yu D, dos Santos CO, Zhao G, et al. miR- 451 protects against erythroid oxidant stress by repressing 14-3-3ζ. Genes Dev. 2010;24(15):1620-1633.
16. Yu D, Carroll M, Thomas-Tikhonenko A. p53 status dictates responses of B lym- phomas to monotherapy with proteasome inhibitors. Blood. 2007;109(11):4936-4943.
17. Gregory T, Yu C, Ma A, Orkin SH, Blobel GA, Weiss MJ. GATA-1 and erythropoietin cooperate to promote erythroid cell sur- vival by regulating bcl-xL expression. Blood. 1999;94(1):87-96.
18. Khandros E, Thom CS, D'Souza J, Weiss MJ. Integrated protein quality-control path- ways regulate free α-globin in murine β-thalassemia. Blood. 2012;119(22):5265- 5275.
19. Cheng Y, Wu W, Kumar SA, et al. Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expres- sion. Genome Res. 2009;19(12):2172-2184.
20. Palis J, Segel GB. Developmental biology of erythropoiesis. Blood Rev. 1998;12(2): 106-114.
21. Godlewski J, Nowicki MO, Bronisz A, et
al. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to meta- bolic stress in glioma cells. Mol Cell. 2010; 37(5):620-632.
22. Shackelford DB, Shaw RJ. The LKB1- AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9(8):563-575.
23. Hawley SA, Boudeau J, Reid JL, et al. Complexes between the LKB1 tumor sup- pressor, STRAD α/β and MO25 α/β are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003;2(4):28.
24. An X, Schulz VP, Li J, et al. Global transcrip- tome analyses of human and murine termi- nal erythroid differentiation. Blood. 2014; 123(22):3466-3477.
25. Dasgupta B, Chhipa RR. Evolving lessons on the complex role of AMPK in normal physiology and cancer. Trends Pharmacol Sci. 2016;37(3):192-206.
26. Ginion A, Auquier J, Benton CR, et al. Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake. Am J Physiol Heart Circ Physiol. 2011; 301(2):H469-H477.
27. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-293.
28. Kwon S, Jeon JS, Ahn C, Sung JS, Choi I. Rapamycin regulates the proliferation of Huh7, a hepatocellular carcinoma cell line, by up-regulating p53 expression. Biochem Biophys Res Commun. 2016;479(1):74-79.
29. Lee JY, Nakada D, Yilmaz OH, et al. mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten dele- tion. Cell Stem Cell. 2010;7(5):593-605.
30. Wang C, Gao D, Guo K, et al. Novel syner- gistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model. BMC Cancer. 2012;12:166.
31. Christophorou MA, Martin-Zanca D, Soucek L, et al. Temporal dissection of p53
10. Dore LC, Amigo JD, Dos Santos CO, et al.
haematologica | 2018; 103(3)
415