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

ABSTRACT: The transcription factor C/EBP? is more potent than C/EBP? 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/EBP?-regulated promoters by wild-type and chimeric C/EBP?/C/EBP? proteins. Wild-type and N-C/EBP?+ C/EBP?-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/EBP? and N-C/EBP?+C/EBP?-DBD had modest effects, although they bound the G-CSFR promoter like wild-type C/EBP? and N-C/EBP?+C/EBP?-DBD. Chimeric proteins consisting of the TAD of VP16 and the DBD of C/EBP? or C/EBP? inhibited proliferation and induced differentiation of K562 cells as effectively as wild-type C/EBP?. Gene expression profiles induced by C/EBP? resembled those modulated by N-C/EBP?+C/EBP?-DBD, whereas C/EBP? induced a pattern similar to that of N-C/EBP?+C/EBP?-DBD. C/EBP? 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/EBP?-regulated gene, was required for apoptosis but not for differentiation induction or proliferation inhibition of K562 cells.

SUBMITTER: Ferrari-Amorotti G 

PROVIDER: S-EPMC2945577 | BioStudies | 2010-01-01T00:00:00Z

REPOSITORIES: biostudies

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