RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements.
The CD11a/CD18 (leukocyte function-associated antigen 1 [LFA-1]) integrin mediates critical leukocyte adhesive interactions during immune and inflammatory responses. The CD11a promoter directs CD11a/CD18 integrin expression, and its activity in lymphoid cells depends on a functional RUNX1/AML-1-binding site (AML-110) within the MS7 sequence. We now report that MS7 contains a C/EBP-binding site (C/EBP-100), which overlaps with AML-110 and is bound by C/EBP factors in myeloid cells. C/EBP and RUNX/AML factors compete for binding to their respective cognate elements and bind to the CD11a promoter MS7 sequence in a cell lineage- and differentiation-dependent manner. In myeloid cells MS7 is primarily recognized by C/EBP factors in proliferating cells whereas RUNX/AML factors (especially RUNX3/AML-2) bind to MS7 in differentiated cells. RUNX3/AML-2 binding to the CD11a promoter correlates with increased RUNX3/AML-2 protein levels and enhanced CD11a/CD18 cell surface expression. The relevance of the AML-110 element is underscored by the ability of AML-1/ETO to inhibit CD11a promoter activity, thus explaining the low CD11a/CD18 expression in t(8;21)-containing myeloid leukemia cells. Therefore, the expression of the CD11a/CD18 integrin in myeloid cells is determined through the differential occupancy of the CD11a proximal promoter by transcription factors implicated in the pathogenesis of myeloid leukemia.
Puig-Kröger
Amaya
A
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Velázquez 144, 28006 Madrid, Spain.
Sanchez-Elsner
Tilman
T
Ruiz
Natividad
N
Andreu
Enrique J
EJ
Prosper
Felipe
F
Jensen
Uffe B
UB
Gil
Juana
J
Erickson
Paul
P
Drabkin
Harry
H
Groner
Yoram
Y
Corbi
Angel L
AL
D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism / Q000502:physiology; D040881:CD11a Antigen / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D005809:Genes, Regulator / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D022762:CCAAT-Enhancer-Binding Proteins; D040881:CD11a Antigen; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors