Effects of Age on the Posttranscriptional Regulation of CCAAT/Enhancer Binding Protein α and CCAAT/Enhancer Binding Protein β Isoform Synthesis in Control and LPS-Treated Livers

Hsieh, Ching Chyuan; Xiong, Wei; Xie, Qizhi; Rabek, Jeffrey P.; Scott, S. G.; An, Mi Ra; Reisner, Peter D.; Kuninger, David; Papaconstantinou, John

doi:10.1091/mbc.9.6.1479

Cited by 59 publications

(83 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The increased response with age to various inducers of stress and inflammation usually has been attributed to abnormal regulation of the levels of systemic mediators. Our findings, however, along with those of other studies, [6][7][8] implicate the cell signaling machinery in the phenomenon. We show that IL-1␤ evokes a more potent JNK response in hepatocytes isolated from aged rats than in hepatocytes isolated from young rats.…”

Section: Discussionsupporting

confidence: 83%

“…5 Aging, however, also affects the cellular response to a variety of agents, including lipopolysaccharide (LPS) and tumor necrosis factor alpha, as well as the response to pharmacological inducers of oxidative stress. [6][7][8] Peritoneal macrophages, hepatocytes, and glial cells isolated from aged animals exhibit more severe and prolonged responses to inflammatory challenges compared with cells originating from young animals. [6][7][8][9] This hyperresponsiveness is manifested in altered activation patterns of cyclooxygenase-2, c-jun N-terminal kinase (JNK), nuclear factor kappa-B, CCAAT/enhancer binding protein alpha, and CCAAT/enhancer binding protein beta.…”

mentioning

confidence: 99%

“…[6][7][8] Peritoneal macrophages, hepatocytes, and glial cells isolated from aged animals exhibit more severe and prolonged responses to inflammatory challenges compared with cells originating from young animals. [6][7][8][9] This hyperresponsiveness is manifested in altered activation patterns of cyclooxygenase-2, c-jun N-terminal kinase (JNK), nuclear factor kappa-B, CCAAT/enhancer binding protein alpha, and CCAAT/enhancer binding protein beta. Hence, changes in the cellular signaling pathways may contribute to the onset of the pro-inflammatory state in aging.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Aging in rat causes hepatic hyperresposiveness to interleukin-1β which is mediated by neutral sphingomyelinase-2

et al. 2007

View full text Add to dashboard Cite

The process of aging has recently been shown to substantially affect the ability of cells to respond to inflammatory challenges. We demonstrate that aging leads to hepatic hyperresponsiveness to interleukin 1␤ (IL-1␤), and we examine the factors that could be responsible for this phenomenon. IL-1␤-induced phosphorylation of c-jun N-terminal kinase (JNK) in hepatocytes isolated from aged rats was 3 times more potent than that in hepatocytes from young rats. Moreover, JNK was activated by substantially lower doses of IL-1␤. These age-related changes in JNK phosphorylation correlated with diminished IL-1␤-induced degradation of interleukin-1 receptor-associated kinase-1 (IRAK-1). Expression levels of IL1␤ receptor I, total JNK, IRAK-1, and transforming growth factor-␤-activated kinase-1 (TAK-1) were not affected by aging. However, increased neutral sphingomyelinase activity was observed in hepatocytes from old animals, which we show is caused by induction of the plasma membrane localized neutral sphingomyelinase-2 (NSMase-2). We provide evidence that NSMase-2 is both required and sufficient for the onset of IL-1␤ hyperresponsiveness during aging. Overexpression of NSMase-2 in hepatocytes from young rats leads both to a reduction in IRAK-1 degradation and potentiation of JNK phosphorylation, mimicking that seen in hepatocytes from old animals. More importantly, inhibition of NSMase activity in hepatocytes from aged rats using either scyphostatin or short interfering ribonucleic acid (siRNA) leads to reversion to the "young" phenotype of IL-1␤ response. Conclusion: These results show that the process of aging causes increased basal NSMase-2 activity in hepatocytes, which in turn leads to IRAK-1 stabilization, JNK potentiation, and ultimately IL-1␤ hyperresponsiveness. (HEPATOLOGY 2007;46:1166-1176

show abstract

Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Aging in rat causes hepatic hyperresposiveness to interleukin-1β which is mediated by neutral sphingomyelinase-2

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that p38, p34, p20, and variable amounts of p14-C/EBP␤ are present in liver extracts (17,18,28,30). These C/EBP␤ isoforms were presumed to arise from alternative translational start sites from within the coding sequence (17).…”

Section: The Appearance Of P20-c/ebp␤ In Cell Extractsmentioning

confidence: 98%

“…1A, lane 7). Previous reports have speculated that translation initiating at Met-207 generates a 14-kDa isoform of C/EBP␤ (18,28). Therefore, we constructed a vector that encodes the C-terminal polypeptide initiating at Met-207 (29) and expressed this protein in HepG2 cells.…”

Section: The Appearance Of P20-c/ebp␤ In Cell Extractsmentioning

confidence: 99%

Generation of Truncated C/EBPβ Isoforms by in VitroProteolysis

Baer

Johnson

2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

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.

show abstract

Activation of a Rel-A/CEBP-?-related transcription factor heteromer by PGG-Glucan in a murine monocytic cell line

Adams

Nathans²,

Pero

et al. 2000

J. Cell. Biochem.

View full text Add to dashboard Cite

PGG-Glucan is a soluble beta-glucan immunomodulator that enhances a variety of leukocyte microbicidal activities without activating inflammatory cytokines. Although several different cell surface receptors for soluble (and particulate) beta-glucans have been described, the signal transduction pathway(s) used by these soluble ligands have not been elucidated. Previously we reported that PGG-Glucan treatment of mouse BMC2.3 macrophage cells activates a nuclear factor kappa-B-like (NF-kappaB) transcription factor complex containing subunit p65 (rel-A) attached to an unidentified cohort. In this study, we identify the cohort to be a non-rel family member: a CCAAT enhancer-binding protein-beta (C/EBP-beta)-related molecule with an apparent size of 48 kDa, which is a different protein than the previously identified C/EBP-beta p34 also present in these cells. C/EBP-beta is a member of the bZIP family whose members have previously been shown to interact with rel family members. This rel/bZIP heteromer complex activated by PGG-Glucan is different from the p65/p50 rel/rel complex induced in these cells by lipopolysaccharide (LPS). Thus, our data demonstrate that PGG-Glucan uses signal transduction pathways different from those used by LPS, which activates leukocyte microbicidal activities and inflammatory cytokines. We further show that heteromer activation appears to use protein kinase C (PKC) and protein tyrosine kinase (PTK) pathways, but not mitogen-activated protein kinase p38. Inhibitor kappa-B-alpha (IkappaB-alpha) is associated with the heteromer; this association decreases after PGG-Glucan treatment. These data are consistent with a model whereby treatment of BMC2.3 cells with PGG-Glucan activates IkappaB-alpha via PKC and/or PTK pathways, permitting translocation of the rel-A/CEBP-beta heteromer complex to the nucleus and increases its DNA-binding affinity.

show abstract

Effects of Age on the Posttranscriptional Regulation of CCAAT/Enhancer Binding Protein α and CCAAT/Enhancer Binding Protein β Isoform Synthesis in Control and LPS-Treated Livers

Cited by 59 publications

References 52 publications

Aging in rat causes hepatic hyperresposiveness to interleukin-1β which is mediated by neutral sphingomyelinase-2

Aging in rat causes hepatic hyperresposiveness to interleukin-1β which is mediated by neutral sphingomyelinase-2

Generation of Truncated C/EBPβ Isoforms by in VitroProteolysis

Activation of a Rel-A/CEBP-?-related transcription factor heteromer by PGG-Glucan in a murine monocytic cell line

Contact Info

Product

Resources

About