C/EBP-beta Regulates Endoplasmic Reticulum Stress-triggered Cell Death in Mouse and Human Models

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Mar 9

PMID 20209087

Citations 33

Authors

Ofir Meir

Efrat Dvash

Ariel Werman

Menachem Rubinstein

Affiliations

Soon will be listed here.

Abstract

Endoplasmic reticulum (ER) stress elicits the unfolded protein response (UPR), initially aimed at coping with the stress, but triggering cell death upon further stress. ER stress induces the C/EBP-beta variant Liver-enriched Activating Protein (LAP), followed by the dominant-negative variant, Liver Inhibitory Protein (LIP). However, the distinct role of LAP and LIP in ER stress is unknown. We found that the kinetics of the ER stress-induced expression of LIP overlapped with that of the cell death in mouse B16 melanoma cells. Furthermore, inducible over-expression of LIP augmented ER stress-triggered cell death whereas over-expression of LAP attenuated cell death. Similar results were obtained in human 293T cells. Limited vasculature in tumors triggers hypoxia, nutrient shortage and accumulation of toxic metabolites, all of which eliciting continuous ER stress. We found that LAP promoted and LIP inhibited B16 melanoma tumor progression without affecting angiogenesis or accelerating the cell cycle. Rather, LAP attenuated, whereas LIP augmented tumor ER stress. We therefore suggest that C/EBP-beta regulates the transition from the protective to the death-promoting phase of the UPR. We further suggest that the over-expression of LAP observed in many solid tumors promotes tumor progression by attenuating ER stress-triggered tumor cell death [corrected].

Citing Articles

The Human Neural Cell Atlas of Zika Infection in developing human brain tissue: viral pathogenesis, innate immunity, and lineage reprogramming.

Stokes C, Whitmore L, Moreno D, Malhotra K, Tisoncik-Go J, Tran E bioRxiv. 2024; .

PMID: 39386476 PMC: 11463344. DOI: 10.1101/2024.09.27.615512.

C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.

Yao Q, Long C, Yi P, Zhang G, Wan W, Rao X CNS Neurosci Ther. 2024; 30(4):e14721.

PMID: 38644578 PMC: 11033503. DOI: 10.1111/cns.14721.

SORCS2 activity in pancreatic α-cells safeguards insulin granule formation and release from glucose-stressed β-cells.

Kalnytska O, Qvist P, Kunz S, Conrad T, Willnow T, Schmidt V iScience. 2024; 27(1):108725.

PMID: 38226160 PMC: 10788290. DOI: 10.1016/j.isci.2023.108725.

An Increase in Peroxiredoxin 6 Expression Induces Neurotoxic A1 Astrocytes in the Lumbar Spinal Cord of Amyotrophic Lateral Sclerosis Mice Model.

Yamamuro-Tanabe A, Mukai Y, Kojima W, Zheng S, Matsumoto N, Takada S Neurochem Res. 2023; 48(12):3571-3584.

PMID: 37556038 DOI: 10.1007/s11064-023-04003-w.

Transcriptomics reveals key genes responsible for functional diversity in muscles of native black Kadaknath and broiler chicken.

Arora R, Sharma R, Ahlawat S, Chhabra P, Kumar A, Kaur M 3 Biotech. 2023; 13(7):253.

PMID: 37396468 PMC: 10310660. DOI: 10.1007/s13205-023-03682-0.

References

Halterman M, de Jesus C, Rempe D, Schor N, Federoff H . Loss of c/EBP-beta activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons. Mol Cell Neurosci. 2008; 38(2):125-37. PMC: 2652244. DOI: 10.1016/j.mcn.2008.01.014. View

Hersey P, Zhang X . Adaptation to ER stress as a driver of malignancy and resistance to therapy in human melanoma. Pigment Cell Melanoma Res. 2008; 21(3):358-67. DOI: 10.1111/j.1755-148X.2008.00467.x. View

Fels D, Ye J, Segan A, Kridel S, Spiotto M, Olson M . Preferential cytotoxicity of bortezomib toward hypoxic tumor cells via overactivation of endoplasmic reticulum stress pathways. Cancer Res. 2008; 68(22):9323-30. PMC: 3617567. DOI: 10.1158/0008-5472.CAN-08-2873. View

Kim I, Xu W, Reed J . Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008; 7(12):1013-30. DOI: 10.1038/nrd2755. View

Li Y, Bevilacqua E, Chiribau C, Majumder M, Wang C, Croniger C . Differential control of the CCAAT/enhancer-binding protein beta (C/EBPbeta) products liver-enriched transcriptional activating protein (LAP) and liver-enriched transcriptional inhibitory protein (LIP) and the regulation of gene expression during the.... J Biol Chem. 2008; 283(33):22443-56. PMC: 2504880. DOI: 10.1074/jbc.M801046200. View

Endl E, Gerdes J . The Ki-67 protein: fascinating forms and an unknown function. Exp Cell Res. 2000; 257(2):231-7. DOI: 10.1006/excr.2000.4888. View

Kokame K, Agarwala K, Kato H, Miyata T . Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress. J Biol Chem. 2000; 275(42):32846-53. DOI: 10.1074/jbc.M002063200. View

Mukherjee D, Kaestner K, Kovalovich K, Greenbaum L . Fas-induced apoptosis in mouse hepatocytes is dependent on C/EBPbeta. Hepatology. 2001; 33(5):1166-72. DOI: 10.1053/jhep.2001.24032. View

EATON E, Hanlon M, Bundy L, Sealy L . Characterization of C/EBPbeta isoforms in normal versus neoplastic mammary epithelial cells. J Cell Physiol. 2001; 189(1):91-105. DOI: 10.1002/jcp.1139. View

10.

Buck M, Poli V, Hunter T, Chojkier M . C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. Mol Cell. 2001; 8(4):807-16. DOI: 10.1016/s1097-2765(01)00374-4. View

11.

Zhu S, Yoon K, Sterneck E, Johnson P, Smart R . CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling. Proc Natl Acad Sci U S A. 2002; 99(1):207-12. PMC: 117540. DOI: 10.1073/pnas.012437299. View

12.

Cortes-Canteli M, Pignatelli M, Santos A, Perez-Castillo A . CCAAT/enhancer-binding protein beta plays a regulatory role in differentiation and apoptosis of neuroblastoma cells. J Biol Chem. 2001; 277(7):5460-7. DOI: 10.1074/jbc.M108761200. View

13.

Bustin M . At the crossroads of necrosis and apoptosis: signaling to multiple cellular targets by HMGB1. Sci STKE. 2002; 2002(151):pe39. DOI: 10.1126/stke.2002.151.pe39. View

14.

Bundy L, Sealy L . CCAAT/enhancer binding protein beta (C/EBPbeta)-2 transforms normal mammary epithelial cells and induces epithelial to mesenchymal transition in culture. Oncogene. 2003; 22(6):869-83. DOI: 10.1038/sj.onc.1206216. View

15.

Lamb J, Ramaswamy S, Ford H, Contreras B, Martinez R, Kittrell F . A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell. 2003; 114(3):323-34. DOI: 10.1016/s0092-8674(03)00570-1. View

16.

Marshall J, Dolan B, Garcia E, Sathe S, Tang X, Mao Z . Calcium channel and NMDA receptor activities differentially regulate nuclear C/EBPbeta levels to control neuronal survival. Neuron. 2003; 39(4):625-39. DOI: 10.1016/s0896-6273(03)00496-3. View

17.

Kamaraju A, Adjalley S, Zhang P, Chebath J, Revel M . C/EBP-delta induction by gp130 signaling. Role in transition to myelin gene expressing phenotype in a melanoma cell line model. J Biol Chem. 2003; 279(5):3852-61. DOI: 10.1074/jbc.M310443200. View

18.

Wessells J, Yakar S, Johnson P . Critical prosurvival roles for C/EBP beta and insulin-like growth factor I in macrophage tumor cells. Mol Cell Biol. 2004; 24(8):3238-50. PMC: 381667. DOI: 10.1128/MCB.24.8.3238-3250.2004. View

19.

Chen C, Dudenhausen E, Pan Y, Zhong C, Kilberg M . Human CCAAT/enhancer-binding protein beta gene expression is activated by endoplasmic reticulum stress through an unfolded protein response element downstream of the protein coding sequence. J Biol Chem. 2004; 279(27):27948-56. DOI: 10.1074/jbc.M313920200. View

20.

Arnett B, Soisson P, Ducatman B, Zhang P . Expression of CAAT enhancer binding protein beta (C/EBP beta) in cervix and endometrium. Mol Cancer. 2003; 2:21. PMC: 155790. DOI: 10.1186/1476-4598-2-21. View