Skip to main content

Advertisement

SpringerLink
Log in

C/EBPαp30, a myeloid leukemia oncoprotein, limits G-CSF receptor expression but not terminal granulopoiesis via site-selective inhibition of C/EBP DNA binding

  • Original Paper
  • Published:
Oncogene Submit manuscript

Abstract

Heterozygous mutations of the CEBPA gene are present in 5% of acute myeloid leukemia (AML) cases and often lead to the expression of an N-terminally truncated, 30 kDa isoform, C/EBPαp30, from an internal translation start site. We have assessed the effect of C/EBPαp30 on granulopoiesis utilizing C/EBPαp30-ER, containing the estradiol receptor ligand-binding domain. In contrast to C/EBPα-ER, C/EBPαp30-ER did not induce 32Dcl3 myeloid cell differentiation in IL-3. However, both isoforms, when expressed at high levels, were capable of inhibiting E2F activity in 32Dcl3 cells and of slowing their G1 to S progression. C/EBPαp30 repressed expression of the endogenous G-CSF receptor several-fold. To facilitate investigation of the effect of C/EBPαp30-ER on granulopoiesis downstream of G-CSF signalling, we coexpressed exogenous G-CSF receptor. C/EBPαp30-ER/GR cells expressed several granulocytic markers in G-CSF and demonstrated nuclear maturation. Rat C/EBPα-ER and C/EBPαp30-ER, expressed in 293T cells, bound the C/EBP site from the NE gene with similar affinity, as did human C/EBPα and C/EBPαp30. In contrast, C/EBPαp30 bound the C/EBP sites in the PU.1 or GR gene with 3–6-fold reduced affinity. Thus, the selective inhibition of GR expression by C/EBPαp30-ER is due in part to its variable affinity for C/EBP sites. Variation in affinity for selected cis elements among isoforms may affect the biology of basic region-leucine zipper (bZIP) proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • An MR, Hsieh CC, Reisner PD, Rabek JP, Scott SG, Kuninger DT and Papaconstantinou J . (1996). Mol. Cell. Biol., 16, 2295–2306.

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

  • Britos-Bray M, Ramirez M, Cao W, Wang X, Liu PP, Civin CI and Friedman AD . (1998). Blood, 92, 4344–4352.

  • Calkhoven CF, Muller C and Leutz A . (2000). Genes Dev., 14, 1920–1932.

  • Christy RJ, Yang VW, Ntambi JM, Geiman DE, Landschulz WH, Friedman AD, Nakabeppu Y, Kelly TJ and Lane MD . (1989). Genes Dev., 3, 1323–1335.

  • Descombes P and Schibler U . (1991). Cell, 67, 569–579.

  • Diehl AM, Michaelson P and Yang SQ . (1994). Gastroenterology, 106, 1625–1637.

  • Friedman AD . (1996). Cancer Res., 56, 3250–3256.

  • 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.

  • Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH, Larsen RJ, Asou H, Miller CW, Hoelzer D and Koeffler HP . (2002). Blood, 99, 1332–1340.

  • Iwasaki-Arai J, Zhang P, Huettner CS, Fenyus M, Lekstrom-Himes J, Tenen DG and Akashi K . (2002). Blood, 100, 61a.

  • Johansen LM, D'Alo' F, Nelson EA, Radomska HS, Evans EK, Zhang P, Nerlov C and Tenen DG . (2003). Blood, in press.

  • Keeshan K, Santill G, Corradini F, Perrotti D and Clabretta B . (2003). Blood, 102, 1267–1275.

  • Kummalue T and Friedman AD . (2003). J. Leuk. Biol., 72, 464–470.

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

  • Lin FT, MacDougland OA, Diehl AM and Lane MD . (1993). Proc. Natl. Acad. Sci. USA, 90, 9606–9610.

  • Liu H, Keefer JR, Wang Q and Friedman AD . (2003). Blood, 101, 3885–3892.

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

  • Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S and Friedman AD . (1994). Mol. Cell. Biol., 14, 5558–5568.

  • Oelgeschläger M, Nuchprayoon I, Luscher 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, Pedersen 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.

  • Rangatia J, Vangala RK, Treiber N, Zhang P, Radomska H, Tenen DG, Hiddemann W and Behre G . (2002). Mol. Cell. Biol., 22, 8681–8694.

  • Raught B, Liao WS and Rosen JM . (1995). Mol. Endocrinol., 9, 1223–1232.

  • Reddy VA, Iwama A, Iotzova G, Schulz M, Elsasser A, Vangala RK, Tenen DG, Hiddemann W and Behre G . (2002). Blood, 100, 483–490.

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

  • Smith LT, Hohaus S, Gonzalez DA, Dziennis SE and Tenen DG . (1996). Blood, 88, 1234–1247.

  • Suzow JG and Friedman AD . (1993). Mol. Cell. Biol., 13, 2141–2151.

  • Theilgaard-Moench K, Ungermand C, Damgaard I, Rasmussen T, Verbeek W, Jacobsen SE, Borregaard N and Porse B . (2002). Blood, 100, 298a.

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

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

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

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

  • Wang W, Wang X, Ward A, Touw I and Friedman AD . (2001b). Leukemia, 15, 779–786.

  • Wang QF, Cleaves R, Kummalue T, Nerlov C and Friedman AD . (2003). Oncogene, 22, 2548–2557.

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

  • Yen J, Wisdom RM, Tratner I and Verma I . (1991). Proc. Natl. Acad. Sci. USA, 88, 5077–5081.

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

  • Zhang P, Iwama A, Datta MW, Darlington GJ, Link DC and Tenen DG . (1998). J. Exp. Med., 188, 1173–1184.

Download references

Acknowledgements

We thank D Tenen, B Porse, and C Nerlov for plasmids and C Stocking for her comparison of rat, mouse, and human C/EBPα sequences. This work was supported by NIH Grant R01 HL51388. ADF is also supported by the Children's Cancer Foundation and is a Scholar of the Leukemia & Lymphoma Society.

Author information

Author notes

  1. Qian-fei Wang

    Present address: Genome Science Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA, 94720, USA

Authors and Affiliations

  1. Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, 21231, MD, USA

    Rebecca Cleaves, Qian-fei Wang & Alan D Friedman

Authors
  1. Rebecca Cleaves
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qian-fei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan D Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan D Friedman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cleaves, R., Wang, Qf. & Friedman, A. C/EBPαp30, a myeloid leukemia oncoprotein, limits G-CSF receptor expression but not terminal granulopoiesis via site-selective inhibition of C/EBP DNA binding. Oncogene 23, 716–725 (2004). https://doi.org/10.1038/sj.onc.1207172

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207172

  • Springer Nature Limited

Keywords

This article is cited by

Search

Navigation