Interferon consensus sequence binding protein (ICSBP) decreases beta-catenin activity in myeloid cells by repressing GAS2 transcription.
The interferon consensus sequence binding protein (ICSBP) is an interferon regulatory transcription factor, also referred to as IRF8. ICSBP acts as a suppressor of myeloid leukemia, although few target genes explaining this effect have been identified. In the current studies, we identified the gene encoding growth arrest specific 2 (GAS2) as an ICSBP target gene relevant to leukemia suppression. We find that ICSBP, Tel, and histone deacetylase 3 (HDAC3) bind to a cis element in the GAS2 promoter and repress transcription in myeloid progenitor cells. Gas2 inhibits calpain protease activity, and beta-catenin is a calpain substrate in these cells. Consistent with this, ICSBP decreases beta-catenin protein and activity in a Gas2- and calpain-dependent manner. Conversely, decreased ICSBP expression increases beta-catenin protein and activity by the same mechanism. This is of interest, because decreased ICSBP expression and increased beta-catenin activity are associated with poor prognosis and blast crisis in chronic myeloid leukemia (CML). We find that the expression of Bcr/abl (the CML oncoprotein) increases Gas2 expression in an ICSBP-dependent manner. This results in decreased calpain activity and a consequent increase in beta-catenin activity in Bcr/abl-positive (Bcr/abl(+)) cells. Therefore, these studies have identified a Gas2/calpain-dependent mechanism by which ICSBP influences beta-catenin activity in myeloid leukemia.
Huang
Weiqi
W
Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
Zhou
Wei
W
Saberwal
Gurveen
G
Konieczna
Iwona
I
Horvath
Elizabeth
E
Katsoulidis
Efstratios
E
Platanias
Leonidas C
LC
Eklund
Elizabeth A
EA
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D020298:U937 Cells; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein; D000099185:Interferon Regulatory Factor-8; D000099186:Histone Deacetylase 3
D016044:Fusion Proteins, bcr-abl; D006655:Histone Deacetylases; D050835:Interferon Regulatory Factors; D008840:Microfilament Proteins; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D051176:beta Catenin; D000097764:ETS Translocation Variant 6 Protein; D000099185:Interferon Regulatory Factor-8; D000099186:Histone Deacetylase 3; C490936:GAS2 protein, human; C099165:Gas2 protein, mouse