AP-1 regulates {alpha}{sub 2}{beta}{sub 1} integrin expression by ERK-dependent signals during megakaryocytic differentiation of K562 cells
- Molecular Cancer Biology Research Program, Biomedicum Helsinki and Haartman Institute, P.O. Box 63, FIN-00014 Helsinki (Finland)
- University of Helsinki, P.O. Box 63, FIN-00014 Helsinki (Finland)
- Molecular Cancer Biology Research Program, Biomedicum Helsinki and Haartman Institute, P.O. Box 63, FIN-00014 Helsinki (Finland) and Department of Oncology, Helsinki University Central Hospital, P.O. Box 180, FIN-00029 HUCH (Finland)
Mitogen-activated protein kinases (MAPKs) have been implicated as regulators of cellular differentiation. The biological effect of MAPK signaling in the nucleus is achieved by signal-responsive transcription factors. Here, we have investigated the connection of MAPKs, transcription factor AP-1, and {alpha}{sub 2}{beta}{sub 1} integrin expression in K562 cells undergoing differentiation along the megakaryocytic pathway. We report that three distinct MAPKs, ERK, JNK, and p38, are activated during the TPA-induced megakaryocytic differentiation. Activation of MAPK pathways is followed by acquisition of the AP-1 DNA-binding and transactivation capacities. AP-1 DNA-binding activity consists primarily of JunD, c-Fos, and Fra-1, and is accompanied with the increased expression and phosphorylation of these subunits. While inhibition of JNK mainly prevents expression and phosphorylation of JunD and c-Jun, inhibition of the ERK pathway suppresses both phosphorylation and expression of Jun proteins, and expression of c-Fos and Fra-1. Furthermore, only the activity of the ERK pathway is essential for the differentiation response, as determined by expression of {alpha}{sub 2}{beta}{sub 1} (CD49b) integrin. The importance of AP-1 as a mediator ERK signaling during differentiation is demonstrated by the findings that expression of c-fos siRNA and dominant negative AP-1/c-Jun{sup bZIP} downregulate the TPA- and ERK-induced expression of {alpha}{sub 2}{beta}{sub 1} integrin mRNAs and proteins. Conversely, coexpression of JunD or c-Jun and c-Fos can induce {alpha}{sub 2}{beta}{sub 1} integrin expression independently of upstream signals. Taken together, the results show that AP-1 is a nuclear target of the ERK-pathway and mediates {alpha}{sub 2}{beta}{sub 1} integrin expression during megakaryocytic differentiation of K562 cells.
- OSTI ID:
- 20717553
- Journal Information:
- Experimental Cell Research, Vol. 304, Issue 1; Other Information: DOI: 10.1016/j.yexcr.2004.10.017; PII: S0014-4827(04)00628-7; Copyright (c) 2004 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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