The biological effects of C/EBPα in K562 cells depend on the potency of the N-terminal regulatory region, not on specificity of the DNA binding domain

Giovanna Ferrari-Amorotti, Samanta Antonella Mariani, Chiara Novi, Sara Cattelani, Luisa Pecorari, Francesca Corradini, Angela Rachele Soliera, Gloria Manzotti, Valentina Fragliasso, Ying Zhang, Robert V. Martinez, Eric W F Lam, Clara Guerzoni, Bruno Calabretta

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Abstract

The transcription factor C/EBPα is more potent than C/EBPβ in inducing granulocitic differentiation and inhibiting BCR/ ABL-expressing cells. We took a "domain swapping" approach to assess biological effects, modulation of gene expression, and binding to C/EBPα-regulated promoters by wild-type and chimeric C/EBPα/C/EBPβ proteins. Wild-type and N-C/EBPα+ C/EBPβ-DBD induced transcription of the granulocyte-colony stimulating factor receptor (G-CSFR) gene, promoted differentiation, and suppressed proliferation of K562 cells vigorously; instead, wild-type C/EBPβ and N-C/EBPβ+C/EBPα-DBD had modest effects, although they bound the G-CSFR promoter like wild-type C/EBPα and N-C/EBPα+C/ EBPβ-DBD. Chimeric proteins consisting of the TAD of VP16 and the DBD of C/EBPα or C/EBPβ inhibited proliferation and induced differentiation of K562 cells as effectively as wild-type C/EBPα. Gene expression profiles induced by C/EBPα resembled those modulated by N-C/EBPα+C/ EBPβ-DBD, whereas C/EBPβ induced a pattern similar to that of N-C/EBPβ+C/EBPα-DBD. C/EBPα activation induced changes in the expression of more cell cycle- and apoptosis-related genes than the other proteins and enhanced Imatinib-induced apoptosis of K562 cells. Expression of FOXO3a, a novel C/EBPα-regulated gene, was required for apoptosis but not for differentiation induction or proliferation inhibition of K562 cells.

Original languageEnglish
Pages (from-to)30837-30850
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number40
DOIs
Publication statusPublished - Oct 1 2010

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Ferrari-Amorotti, G., Mariani, S. A., Novi, C., Cattelani, S., Pecorari, L., Corradini, F., Soliera, A. R., Manzotti, G., Fragliasso, V., Zhang, Y., Martinez, R. V., Lam, E. W. F., Guerzoni, C., & Calabretta, B. (2010). The biological effects of C/EBPα in K562 cells depend on the potency of the N-terminal regulatory region, not on specificity of the DNA binding domain. Journal of Biological Chemistry, 285(40), 30837-30850. https://doi.org/10.1074/jbc.M110.128272