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RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory
Amaya Puig-Kröger1, Tilman Sanchez-Elsner, Natividad Ruiz
1Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Velázquez 144, 28006 Madrid, Spain.
Blood
|July 12, 2003
Summary
Transcription factors C/EBP and RUNX/AML compete for binding to the CD11a promoter in myeloid cells. This differential binding controls CD11a/CD18 integrin expression, impacting myeloid leukemia pathogenesis.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- The CD11a/CD18 integrin (leukocyte function-associated antigen 1 [LFA-1]) is crucial for leukocyte adhesion in immune responses.
- CD11a promoter activity, particularly in lymphoid cells, relies on the RUNX1/AML-1-binding site (AML-110) within the MS7 sequence.
Purpose of the Study:
- To investigate the role of transcription factor binding to the CD11a promoter MS7 sequence in myeloid cells.
- To elucidate how differential transcription factor binding influences CD11a/CD18 integrin expression and its relevance in myeloid leukemia.
Main Methods:
- Analysis of transcription factor binding sites within the CD11a promoter MS7 sequence.
- Investigation of C/EBP and RUNX/AML factor binding in different myeloid cell lineages and differentiation states.
- Correlation of transcription factor binding with CD11a/CD18 cell surface expression levels.
Main Results:
- The MS7 sequence contains a C/EBP-binding site (C/EBP-100) that overlaps with the AML-110 site and is recognized by C/EBP factors in myeloid cells.
- C/EBP and RUNX/AML factors compete for MS7 binding in a cell lineage- and differentiation-dependent manner.
- In myeloid cells, C/EBP factors bind in proliferating cells, while RUNX/AML factors (especially RUNX3/AML-2) bind in differentiated cells, correlating with increased CD11a/CD18 expression.
- AML-1/ETO binding inhibits CD11a promoter activity, explaining low CD11a/CD18 expression in t(8;21) myeloid leukemia.
Conclusions:
- Myeloid cell CD11a/CD18 integrin expression is regulated by the differential occupancy of the CD11a proximal promoter by specific transcription factors.
- These transcription factors, including C/EBP and RUNX/AML, are implicated in the pathogenesis of myeloid leukemia, highlighting a molecular mechanism linking transcription factor activity to disease.