CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein.

Timchenko, Nikolai A.; Wilde, Margie; Nakanishi, Makoto; Smith, James R.; Darlington, Gretchen J.

doi:10.1101/gad.10.7.804

Cited by 367 publications

(386 citation statements)

References 39 publications

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“…Similar uncoupling of protein and mRNA expression has been observed for other genes in the regenerating liver (Albrecht et al, 1995;Greenbaum et al, 1995), and suggests regulation at the level of translation or protein stability. Regulation of p21 expression at the level of protein stability has been recently documented (Blagosklonny et al, 1996); the stability of p21 protein can be enhanced by the transcription factor c/EBPa, leading to growth inhibition in ®brosarcoma cells (Timchenko et al, 1996). Therefore, altered protein stability during liver regeneration might explain the discordance between p21 mRNA and protein, but this mechanism requires further examination.…”

Section: Discussionmentioning

confidence: 99%

Involvement of p21 and p27 in the regulation of CDK activity and cell cycle progression in the regenerating liver

et al. 1998

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In tissue culture systems, p21 and p27 inhibit cyclindependent kinase (CDK) activity and cell cycle progression in response to numerous stimuli, but little is known about their involvement in cell growth in vivo. We examined the modulation of CDK activity by these proteins after 70% partial hepatectomy (PH), an in vivo model of synchronous hepatocyte cell cycle progression. After PH in BALB/c mice, p21 was induced during the prereplicative (G1) phase and was maximally expressed after peak hepatocyte DNA synthesis. p27 was present in quiescent liver and was minimally induced after PH. p21 and p27 immunoprecipitated with CDK2, CDK4, and cyclin D1 in the regenerating liver. The activity of CDK2-, CDK4-and cyclin D1-associated kinases was upregulated after PH, and maximal activity of these enzyme complexes corresponded to peak DNA synthesis. Immunodepletion experiments suggested that p27 plays a role in downregulating CDK2 activity before and after peak DNA synthesis. Compared to cogenic wild-type mice, p217/7 mice demonstrated evidence of markedly accelerated hepatocyte progression through G1 phase after PH: DNA synthesis, upregulation of cyclin A and PCNA, induction of cyclin D1-and CDK2-associated kinase activity, and appearance of a phosphorylated retinoblastoma protein (Rb) species occurred earlier in the p217/7 mice. These results suggest that p21 and p27 modulate CDK activity in the regenerating liver, and that p21 regulates the rate of progression through G1 phase of the cell cycle in vivo.

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Section: Discussionmentioning

confidence: 99%

Involvement of p21 and p27 in the regulation of CDK activity and cell cycle progression in the regenerating liver

et al. 1998

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“…Increased calreticulin expression is correlated with the suppression of the granulocytic differentiation factor CEBPA in AML with inv(16) and t(8;21); calreticulin is also reported to interact with C/EBPalpha and C/EBPbeta mRNA and represses them at protein level (Helbling et al, 2004;Helbling et al, 2005). AML patients positive for t(8;21) have undetectable C/EBP alpha protein as compared to other subgroups of AML patients (Timchenko et al, 1996(Timchenko et al, , 2002. These effects may be in part owing to the acetylation of calreticulin in t(8;21) which we reported here and not because of the nascent calreticulin protein alone.…”

Section: Discussionmentioning

confidence: 99%

Proteomics of acute myeloid leukaemia: cytogenetic risk groups differ specifically in their proteome, interactome and post-translational protein modifications

et al. 2006

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Acute myeloid leukaemia (AML) is characterized by specific cytogenetic aberrations that are strong determinants of prognostic outcome and therapeutic response. Because the pathological outcome of AML patients with cytogenetic abnormalities differs considerably, we hypothesized that their proteome may also differ specifically in their expression pattern, protein interaction pathways and post-translational modifications (PTM). We performed this study using 42 AML patients diagnosed for various cytogenetic abnormalities based on two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MS) and MSMS tandem MS. We could identify significant differences in the proteome and PTM of peptides, later confirmed by other methods, between cytogenetic groups. The interactome analysis based on computational bioinformatics reveals major regulating networks: MAPK8 and MYC for complex aberrant karyotype, TP53 for t(8;21), TP53-MYC-PRKAC for 11q23 and JUN and MYC for Inv(16). Further, we analysed 42 MS spectra representative of hnRNPH1, calreticulin and hnRNPA2/B1 in a peak explorer, which reveals a cytogenetic-specific PTM of b-O-linked N-acetyl glucosamine (O-GlcNAc) of hnRNPH1 in AML patients with 11q23 translocation, an acetylation of calreticulin in t(8;21) translocation and methylation of hnRNPA2/B1 in patients with translocations of t(8;21) and inv(16). This report may lead to a new thinking about AML pathogenesis, as differences at PTM level could be used to distinguish different subtypes of AML.

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“…75 In various cell types, other investigators have suggested that the transcription factors Sp3, C/EBP␣, C/EBP␤, Stat1, and p300 may also play a role in this process. [76][77][78][79][80] Thus the precise transcription factor mediators of MAP kinase signaling to the p21 Cip-1/MDA6/WAF1 promoter are not fully described in any one cell type. Futhermore, based on the several reports showing regulation of p21 Cip-1/MDA6/WAF1 in response to increased or decreased MAP kinase signaling, it is very likely that the roles of transcription factors in regulating p21 Cip-1/MDA6/WAF1 expression may be cell type specific.…”

Section: An Overview For the Role Of The Map Kinase Pathway In Prolifmentioning

confidence: 99%

The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity

et al. 1998

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During the last 10 years, multiple signal transduction pathways within cells have been discovered. These pathways have been linked to the regulation of many diverse cellular events such as proliferation, senescence, differentiation and apoptosis. This review will focus upon the many roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway. Recent evidence suggests that signaling by the MAP kinase pathway can both enhance proliferation by increased expression of molecules such as cyclin D1, but also cause growth arrest by increased expression of molecules such as the cyclin kinase inhibitor protein p21 Cip-1/MDA6/WAF1 . These differential effects on growth have been correlated to the amplitude and duration of the MAP kinase activity signal. Furthermore several laboratories are reporting data suggesting that inhibition of the MAP kinase pathway, as well as a family of upstream MAP kinase activators, the protein kinase C family, represent an important route to both radio-and chemo-sensitization of tumor cells. Herein, we describe the historical discovery and characterization of the MAP kinase pathway. In addition we describe potential mechanisms by which inhibition of protein kinase C, the MAP kinase pathway, and potentially of p21 Cip-1/MDA6/WAF1 expression, may alter the sensitivities of leukemic and carcinoma cells to cytotoxic insults, leading to increased apoptosis and loss of clonogenicity.

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CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein.

Cited by 367 publications

References 39 publications

Involvement of p21 and p27 in the regulation of CDK activity and cell cycle progression in the regenerating liver

Involvement of p21 and p27 in the regulation of CDK activity and cell cycle progression in the regenerating liver

Proteomics of acute myeloid leukaemia: cytogenetic risk groups differ specifically in their proteome, interactome and post-translational protein modifications

The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity

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