This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paz-Priel, I. Articles by Friedman, A. D. Search for Related Content PubMed PubMed Citation Articles by Paz-Priel, I. Articles by Friedman, A. D.

---

Signaling and Regulation

CCAAT/Enhancer Binding Protein (C/EBP) and C/EBP Myeloid Oncoproteins Induce Bcl-2 via Interaction of Their Basic Regions with Nuclear Factor-B p50

Divisions of ¹ Pediatric Oncology and ² Oncology Biostatistics, Johns Hopkins University, Baltimore, Maryland; ³ Department of Medicine, Stanford University, Stanford, California; and ⁴ Hematology/Oncology, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Alan D. Friedman, Division of Pediatric Oncology, Johns Hopkins University, CRB 253, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410-955-2095; Fax: 410-955-8897. E-mail: afriedm2{at}jhmi.edu

The CEBPA gene is mutated in 10% of acute myeloid leukemia (AML) cases. We find that CEBPA and Bcl-2 RNA levels correlate highly in low-risk human AMLs, suggesting that inhibition of apoptosis via induction of bcl-2 by CCAAT/enhancer binding protein (C/EBP) or its mutant variants contributes to transformation. C/EBPp30, lacking a NH₂-terminal transactivation domain, or C/EBPLZ, carrying in-frame mutations in the leucine zipper that prevent DNA binding, induced bcl-2 in hematopoietic cell lines, and C/EBP induced bcl-2 in normal murine myeloid progenitors and in the splenocytes of H2K-C/EBP-Eµ transgenic mice. C/EBP protected Ba/F3 cells from apoptosis on interleukin-3 withdrawal but not if bcl-2 was knocked down. Remarkably, C/EBPLZ oncoproteins activated the bcl-2 P2 promoter despite lack of DNA binding, and C/EBPp30 also activated the promoter. C/EBP and the C/EBP oncoproteins cooperated with nuclear factor-B (NF-B) p50, but not p65, to induce bcl-2 transcription. Endogenous C/EBP preferentially coimmunoprecipitated with p50 versus p65 in myeloid cell extracts. Mutation of residues 297 to 302 in the C/EBP basic region prevented induction of endogenous bcl-2 or the bcl-2 promoter and interaction with p50 but not p65. These findings suggest that C/EBP or its mutant variants tether to a subset of NF-B target genes, including Bcl-2, via p50 to facilitate gene activation and offer an explanation for preferential in-frame rather than out-of-frame mutation of the leucine zipper with sparing of the basic region in C/EBPLZ oncoproteins. Targeting interaction between C/EBP basic region and NF-B p50 may contribute to the therapy of AML and other malignancies expressing C/EBPs.

This article has been cited by other articles:

				M. Han, W. Yan, Y. Huang, H. Yao, Z. Wang, D. Xi, W. Li, Y. Zhou, J. Hou, X. Luo, et al. The Nucleocapsid Protein of SARS-CoV Induces Transcription of hfgl2 Prothrombinase Gene Dependent on C/EBP Alpha J. Biochem., July 1, 2008; 144(1): 51 - 62. [Abstract] [Full Text] [PDF]

				L. Zhang, F. B. Fried, H. Guo, and A. D. Friedman Cyclin-dependent kinase phosphorylation of RUNX1/AML1 on 3 sites increases transactivation potency and stimulates cell proliferation Blood, February 1, 2008; 111(3): 1193 - 1200. [Abstract] [Full Text] [PDF]

				M. Geletu, M. Y. Balkhi, A. A. Peer Zada, M. Christopeit, J. A. Pulikkan, A. K. Trivedi, D. G. Tenen, and G. Behre Target proteins of C/EBP{alpha}p30 in AML: C/EBP{alpha}p30 enhances sumoylation of C/EBP{alpha}p42 via up-regulation of Ubc9 Blood, November 1, 2007; 110(9): 3301 - 3309. [Abstract] [Full Text] [PDF]

				T. N. Jorgensen, A. McKee, M. Wang, E. Kushnir, J. White, Y. Refaeli, J. W. Kappler, and P. Marrack Bim and Bcl-2 Mutually Affect the Expression of the Other in T Cells J. Immunol., September 15, 2007; 179(6): 3417 - 3424. [Abstract] [Full Text] [PDF]

				T. Akasaka, T. Balasas, L. J. Russell, K.-j. Sugimoto, A. Majid, R. Walewska, E. L. Karran, D. G. Brown, K. Cain, L. Harder, et al. Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) Blood, April 15, 2007; 109(8): 3451 - 3461. [Abstract] [Full Text] [PDF]

				L. Zheng, S. J. Howell, D. A. Hatala, K. Huang, and T. S. Kern Salicylate-Based Anti-Inflammatory Drugs Inhibit the Early Lesion of Diabetic Retinopathy Diabetes, February 1, 2007; 56(2): 337 - 345. [Abstract] [Full Text] [PDF]

				U. Testa and R. Riccioni Deregulation of apoptosis in acute myeloid leukemia Haematologica, January 1, 2007; 92(1): 81 - 94. [Abstract] [Full Text] [PDF]

				D. Wang, J. D'Costa, C. I. Civin, and A. D. Friedman C/EBP{alpha} directs monocytic commitment of primary myeloid progenitors Blood, August 15, 2006; 108(4): 1223 - 1229. [Abstract] [Full Text] [PDF]