The Mechanism Study Of FAM122A Inhibiting Erythroid Differentiation

Erythrocytic differentiation and maturation are essential for maintaining the numbers and functions of normal red blood cells(RBCs)in healthy adults.Erythropoiesis is a dynamic and complex process which is finely manipulated by a series of lineage-specific transcription factors.GATA1 is the master transcription factor for erythropoiesis and abnormal regulation of GATA1 results in dyserythropoiesis disorders.Thus,the strategy of GATA1 as a therapeutic target is beneficial to control the occurrence and progress of erythroid development-related diseases.FAM122A,a housekeeping gene,is highly conserved among a variety of mammalian species.Previously we reported that FAM122A inhibits the phosphatase activity of protein phosphatases of type 2A family(PP2A).More recently,we demonstrated that FAM122A is critical for maintaining cell growth of hepatocellular carcinoma(HCC)and acute myeloid leukemia(AML)cells.However,so far the biological function of FAM122A protein is still pooly understood.In this study,we found that FAM122A is down-regulated during terminal erythroid differentiation,and significantly inhibits erythrocytic differentiation by using the in vitro differentiation induction model with erythropoietin(hEPO)or hemin treatment in human hematopoietic stem progenitor cells(CD34+cells)and two erythroleukemia cells(K562 and HEL cells).Mechanically,FAM122A interacts directly with GATA1 by its C-terminal zinc finger domain,resulting in the reduction of the DNA binding and transcriptional activity of GATA1,thus blocking erythroid differentiation.On the other hand,we found that FAM122A is required for maintaining ERK/AKT/STAT5 signaling activity,since FAM122A deletion significantly reduces the phosphorylation levels of ERK,AKT and STAT5 proteins which are direct targets of PP2A,suggesting that the effect of FAM122A on erythroid differentiation is also possibly by modulating PP2A activity.More importantly,the suppression of ERK/AKT/STAT5 activation upon FAM122A silencing is accompanied with the significant growth reduction during hEPO-induced erythroid differentiation of CD34+cells,which is consistent with the evidence showing that ERK/AKT/STAT5 signaling is required for the survival and proliferation of erythroid progenitor cells.Collectively,our studies indicate that FAM122A plays an inhibitory role in the regulation of erythroid differentiation,and would be a new potentially therapeutic target for GATA1-related diseases or dyserythropoietic disorders.