Translation start site multiplicity of the CCAAT/enhancer binding protein α mRNA is dictated by a small 5′ open reading frame

Calkhoven, Cornelis F.; Bouwman, Peter; Snippe, Lenie; Ab, Geert

doi:10.1093/nar/22.25.5540

Cited by 78 publications

(96 citation statements)

References 39 publications

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“…Both of the transcripts also contain short upstream open reading frames (uORFs) located in the 5Ј leader, immediately upstream of the major open reading frames (20 -22). Since uORFs can inhibit translation from downstream AUG codons, it was suggested that the uORF elements are involved in regulating expression of the truncated isoforms (21). In support of this notion, the presence of the C/EBP␣ and C/EBP␤ 5Ј leader regions was reported to increase expression of the p30-C/EBP␣ (15,16) and p20-C/EBP␤/LIP (17) polypeptides in transiently transfected cells.…”

Section: C/ebp␤mentioning

confidence: 95%

“…within the 5Ј leader region of the transcript (21). To examine the effect of the 5Ј leader on production of the various C/EBP␤ isoforms, we used C/EBP␤ expression vectors in which the 5Ј leader sequences were either present (uORF-C/EBP␤) or were replaced by a consensus translation initiation signal (pMEX-C/ EBP␤).…”

Section: The C/ebp␤ 5ј Leader Region Does Not Significantly Increase mentioning

confidence: 99%

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Generation of Truncated C/EBPβ Isoforms by in VitroProteolysis

Baer

Johnson

2000

Journal of Biological Chemistry

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Multiple forms of the transcriptional regulator CCAAT/enhancer-binding protein ␤ (C/EBP␤) with molecular masses of approximately 38, 34, 20, and 14 kDa have been observed in cell extracts. It has been proposed that these proteins arise by alternative initiation at in-frame AUG codons. The truncated C/EBP␤ isoforms (p14 and p20/LIP) lack transactivation domains but retain DNA-binding and dimerization sequences and are therefore assumed to function as competitive inhibitors of C/EBP-mediated transcription in vivo. By comparing various extraction procedures to analyze endogenous and overexpressed C/EBP␤ proteins, we determined that p20-C/EBP␤ is generated predominantly by in vitro proteolytic cleavage during isolation from cells and that p14-C/EBP␤ is produced exclusively by this mechanism. In transfected cells, the full-length (p34 and p38) isoforms but not the truncated proteins were detectable in the cytoplasm, indicating that the latter are not primary translation products. In addition, the C/EBP␤ leucine zipper dimerization domain was essential for the appearance of the truncated species, demonstrating that protein folding or dimerization are critical determinants of proteolytic sensitivity. Our findings suggest that the presence of truncated C/EBP␤ proteins in cell extracts must be interpreted with caution and that assumptions about the in vivo relevance of these isoforms should be re-evaluated.

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Section: C/ebp␤mentioning

confidence: 95%

Section: The C/ebp␤ 5ј Leader Region Does Not Significantly Increase mentioning

confidence: 99%

Generation of Truncated C/EBPβ Isoforms by in VitroProteolysis

Baer

Johnson

2000

Journal of Biological Chemistry

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“…This shorter form of CEBPA lacks antiproliferative activity 35 and most of the transactivation properties of the normal protein, 36,37 and acts dominantly on wt CEBPA by inhibiting DNA binding of CEBPA on targeted genes. 3 Indeed, in the presence of equal amounts of 42-kDa and 30-kDa in vitro, the 30-kDa isoform totally abolished transactivation of a plasmid reporter by the full-length CEBPA protein.…”

Section: Pathogenetic Role Of Cebpa Mutationsmentioning

confidence: 99%

CEBPA point mutations in hematological malignancies

et al. 2005

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The CCAAT/enhancer-binding protein-alpha (CEBPA) is a transcription factor strongly implicated in myelopoiesis through control of proliferation and differentiation of myeloid progenitors. Recently, several works have reported the presence of CEBPA-acquired mutations in hematological malignancies. In this work, we analyzed characteristics of mutations and their correlation with disease characteristics described in previous studies. In the 1175 patients reported, 146 CEBPA mutations were identified in 96 patients. Mutations were found in the whole gene sequence, but cluster regions were clearly identified. Furthermore, two categories of mutations were reported: out-of-frame ins/del often in the N-terminal region, and in-frame ins/del often in the C-terminal region. CEBPA mutations were reported exclusively in acute myeloid leukemia (AML) (according to WHO classification criteria) and mutated patients preferentially belonged to M1, M2 and M4 FAB subtypes. All but one case belonged to the 'intermediate' prognostic subgroup of MRC classification. In the absence of poor prognostic factors, patients with CEBPA mutation had favorable outcome, very similar to that of the t(8;21), inv(16), t(15;17) subgroup. Systematic analysis of CEBPA mutations, in addition to that of alterations in master genes of hematopoiesis, may be useful to assess the prognosis of AML particularly in patients belonging to the 'intermediate' prognostic subgroup.

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“…These proteins most likely represent di erent isoforms generated by the utilization of multiple translation initiation sites present in the C/ EBPb mRNA (Calkhoven et al, 1994;Kowenz-Leutz and Leutz, 1999;Timchenko et al, 1999). The predominant form observed in CEF and expressed by the recombinant C/EBPb retrovirus is the 42 kDa protein.…”

Section: C/ebpb Is Required For the Activation Of The Cef-4 Srumentioning

confidence: 99%