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  • Original Paper
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Cell cycle inhibition mediated by the outer surface of the C/EBPα basic region is required but not sufficient for granulopoiesis

Abstract

CCAAT/enhancer binding protein α (C/EBPα) transactivates target genes dependent upon DNA binding via its basic region-leucine zipper domain and slows G1 progression by interaction with E2F, cdk2, or cdk4. E2F interacts with the non-DNA-binding surface of the C/EBPα basic region and C/EBPα residues 1–70 are required for repressing E2F targets, while cdk2 and cdk4 bind residues 177–191. C/EBPα-ER induces the 32D cl3 myeloblast cell line to differentiate to granulocytes. C/EBPα-ER variants incapable of binding DNA slowed G1, but did not induce early or late granulopoiesis, indicating that cell cycle inhibition as mediated by C/EBPα is not sufficient for differentiation. C/EBPα-ER variants lacking residues 11–70 or residues 11–70 and 178–200 both slowed the G1 to S transition. C/EBPα(GZ)-ER, containing the GCN4 rather than the C/EBPα leucine zipper, also slowed G1. In contrast, C/EBPα(BRM2)-ER, carrying mutations in the outer surface of the basic region required for interaction with E2F, did not slow G1. C/EBPα(BRM2)-ER induced early markers of granulopoiesis much less efficiently than C/EBPα-ER and did not direct terminal maturation. Inhibition of G1 progression using mimosine increased induction of late markers by G-CSF. Thus, both DNA binding and cell cycle arrest, mediated by opposite surfaces of the C/EBPα basic region, are required for granulopoiesis.

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References

  • Anfossi G, Gewirtz AM and Calabretta B . (1989). Proc. Natl. Acad. Sci. USA, 86, 3379–3383.

  • Antonson P and Xanthopoulos KG . (1995). Biochem. Biophys. Res. Commun., 215, 105–113.

  • Bies J, Mukhopadhyaya R, Pierce J and Wolff L . (1995). Cell. Growth Differ., 6, 59–68.

  • Birkenmeier EH, Gwyenn B, Howard S, Jerry J, Gordon JI, Landschulz WH and McKnight SL . (1989). Genes Dev., 3, 1146–1156.

  • Britos-Bray M and Friedman AD . (1997). Mol. Cell. Biol., 17, 5127–5135.

  • Cao W, Britos-Bray M, Claxton DF, Kelley CA, Speck NA, Liu PP and Friedman AD . (1997). Oncogene, 15, 1315–1327.

  • Chandrasekaran C and Gordon JI . (1993). Proc. Natl. Acad. Sci. USA, 90, 8871–8875.

  • Chen PL, Riley DJ, Chen-Kiang S and Lee WH . (1996). Proc. Natl. Acad. Sci. USA, 93, 465–469.

  • Clarke MF, Kukowska LJ, Westin E, Smith M and Prochownik EV . (1988). Mol. Cell. Biol. 8, 884–892.

  • Crescenzi M, Fleming TP, Lassar AB, Weintraub H and Aaronson SA . (1990). Proc. Natl. Acad. Sci. USA, 87, 8442–8446.

  • Danos O and Mulligan RC . (1988). Proc. Natl. Acad. Sci. USA, 85, 6460–6464.

  • Friedman AD . (2002a). Oncogene, 21, 3377–3390.

  • Friedman AD . (2002b). J. Cell. Biochem., 86, 624–629.

  • Friedman AD, Landschulz WH and McKnight SL . (1989). Genes Dev., 3, 1314–1322

  • Friedman AD and McKnight SL . (1990). Genes Dev., 4, 1416–1426.

  • Gewirtz AM, Anfossi G, Venturelli D, Valpreda S, Sims R and Calabretta B . (1989). Science, 245, 180–183.

  • Hagemeier C, Bannister AJ, Cook A and Kouzarides T . (1993). Proc. Natl. Acad. Sci. USA, 90, 1580–1584.

  • Hsu W, Kerpola TK, Chen P-L, Curran T and Chen-Kiang S . (1994). Mol. Cell. Biol., 14, 268–276.

  • Johansen LM, Iwama A, Lodie TA, Sasaki K, Felsher DW, Golub TR and Tenen DG . (2001). Mol. Cell. Biol., 21, 3789–3806.

  • Johnson PF, Landschulz, Graves BJ and McKnight SL . (1987). Genes Dev., 1, 133–146.

  • Kato J-Y and Sherr CJ . (1993). Proc. Natl. Acad. Sci. USA, 90, 11513–11517.

  • Landschulz WH, Johnson PF and McKnight SL . (1989). Science, 246, 1681–1688.

  • Liu M, Lee M-H, Cohen M, Bommakanti M and Freedman LP . (1996). Genes Dev., 10, 142–153.

  • Lou J, Cao W, Bernardin F, Ayyanathan K, Rauscher III FJ and Friedman AD . (2000). Oncogene, 19, 2695–2703.

  • Muller C, alunni-Fabbroni M, Kowenz-Leutz E, Mo X, Tommasino M and Leutz A . (1999). Proc. Natl. Acad. Sci. USA, 96, 7276–7281.

  • Nerlov C and Ziff EB . (1994). Genes Dev., 8, 350–362.

  • Oelgeschläger M, Nuchprayoon I, Lüscher B and Friedman AD . (1996). Mol. Cell. Biol., 16, 4717–4725.

  • Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, Behre G, Hiddemann W and Tenen DG . (2001). Nat. Genet., 27, 263–270.

  • Porse BT, Pederson TA, Xu X, Lindberg B, Wewer UM, Friis-Hansen L and Nerlov C . (2001). Cell, 107, 247–258.

  • Radomska HS, Huettner CS, Zhang P and Tenen DG . (1998). Mol. Cell. Biol., 18, 4301–4314.

  • Scott LM, Civin CI, Rorth P and Friedman AD . (1992). Blood, 80, 1725–1735.

  • Slomiany BA, D'Arigo KL, Kelly MM and Kurtz DT . (2000). Mol. Cell. Biol., 20, 5986–5997.

  • Strom DK, Cleveland JL, Chellappan S, Nip J and Hiebert SW . (1998). Cell Growth Differ., 9, 59–69.

  • Timchenko NA, Wilde M and Darlington GJ . (1999). Mol. Cell. Biol., 19, 2936–2945.

  • Umek RM, Friedman AD and McKnight SL . (1991). Science, 251, 288–292.

  • Valtieri M, Tweardy DJ, Caracciolo D, Johnson K, Mavilio F, Altman S, Snatoli D and Rovera G . (1987). J. Immunol., 138, 3829–3835.

  • Vinson CR, Sigler PB and McKnight SL . (1989). Science, 246, 911–916.

  • Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD, Taylor LR, Wilson DR and Darglington DG . (1995). Science, 269, 1108–1112.

  • Wang Q and Friedman AD . (2002). Blood, 99, 2776–2785.

  • Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ and Timchenko NA . (2001). Cell, 8, 817–828.

  • Wang G, Miskimins R and Miskimins WK . (2000). Exp. Cell Res., 254, 64–71.

  • Wang X, Scott E, Sawyers CL and Friedman AD . (1999). Blood, 94, 560–571.

  • Zhang D-E, Zhang P, Wang N-D, Hetherington CJ, Darlington GJ and Tenen DG . (1997). Proc. Natl. Acad. Sci. USA, 94, 569–574.

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Acknowledgements

This work was supported by National Institutes of Health Grants R01 HL62274 and HL62274 to ADF. ADF is a Leukemia and Lymphoma Society Scholar and is also supported by the Children's Cancer Foundation.

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Correspondence to Alan D Friedman.

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Wang, QF., Cleaves, R., Kummalue, T. et al. Cell cycle inhibition mediated by the outer surface of the C/EBPα basic region is required but not sufficient for granulopoiesis. Oncogene 22, 2548–2557 (2003). https://doi.org/10.1038/sj.onc.1206360

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