EurekaMag.com logo
+ Site Statistics
References:
53,869,633
Abstracts:
29,686,251
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on LinkedInFollow on LinkedIn

+ Translate

Protein kinase Cepsilon activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-alpha-induced cell death



Protein kinase Cepsilon activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-alpha-induced cell death



Journal of Biological Chemistry 281(32): 22799-22807



We have previously shown that protein kinase Cepsilon (PKCepsilon) protects breast cancer cells from tumor necrosis factor-alpha (TNF)-induced cell death. In the present study, we have investigated if the antiapoptotic function of PKCepsilon is mediated via Akt and the mechanism by which PKCepsilon regulates Akt activity. TNF caused a transient increase in Akt phosphorylation at Ser473 in MCF-7 cells. Overexpression of PKCepsilon in MCF-7 cells increased TNF-induced Akt phosphorylation at Ser473 resulting in its activation. Knockdown of PKCepsilon by small interfering RNA (siRNA) decreased TNF-induced Akt phosphorylation/activation and increased cell death. Introduction of constitutively active Akt protected breast cancer MCF-7 cells from TNF-mediated cell death and partially restored cell survival in PKCepsilon-depleted cells. Depletion of Akt in MCF-7 cells abolished the antiapoptotic effect of PKCepsilon on TNF-mediated cell death. Akt was constitutively associated with PKCepsilon and DNA-dependent protein kinase (DNA-PK), and this association was increased by TNF treatment. Overexpression of PKCepsilon enhanced the interaction between Akt and DNA-PK. Knockdown of DNA-PK by siRNA inhibited TNF-induced Akt phosphorylation and the antiapoptotic effect of Akt and PKCepsilon. These results suggest that PKCepsilon activates Akt via DNA-PK to mediate its antiapoptotic function. Furthermore, we report for the first time that DNA-PK can regulate receptor-initiated apoptosis via Akt.

(PDF emailed within 0-6 h: $19.90)

Accession: 050054774

Download citation: RISBibTeXText

PMID: 16785234

DOI: 10.1074/jbc.M603390200



Related references

Protein kinase Cepsilon is linked to 12-O-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor-alpha ectodomain shedding and the development of metastatic squamous cell carcinoma in protein kinase Cepsilon transgenic mice. Cancer Research 63(19): 6547-6555, 2003

Regulation of tumor necrosis factor-alpha-induced cell death by protein kinase C and p70 S6 kinase. Proceedings of the American Association for Cancer Research Annual Meeting 43: 883, March, 2002

Tumor necrosis factor alpha activates a serine threonine protein kinase distinct from protein kinase c in mesangial cells. Journal of the American Society of Nephrology 2(3): 463, 1991

The streptococcal exotoxin streptolysin O activates mast cells to produce tumor necrosis factor alpha by p38 mitogen-activated protein kinase- and protein kinase C-dependent pathways. Infection and Immunity 71(11): 6171-6177, 2003

Overexpression of protein kinase C-eta attenuates caspase activation and tumor necrosis factor-alpha-induced cell death. Biochemical and Biophysical Research Communications 279(1): 103-107, 2000

Evidence that protein kinase Cepsilon mediates phorbol ester inhibition of calphostin C- and tumor necrosis factor-alpha-induced apoptosis in U937 histiocytic lymphoma cells. Journal of Biological Chemistry 273(37): 24115-24121, 1998

Tumor necrosis factor alpha rapidly activates the mitogen-activated protein kinase (MAPK) cascade in a MAPK kinase kinase-dependent, c-Raf-1-independent fashion in mouse macrophages. Proceedings of the National Academy of Sciences of the United States of America 92(5): 1614-1618, 1995

Tumor necrosis factor signaling to stress-activated protein kinase /Jun NH2-terminal kinase and p38 Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. Journal of Biological Chemistry 273(35): 22681-22692, Aug 28, 1998

Involvement of protein kinase C and protein tyrosine kinase pathways in tumor necrosis factor-alpha-induced clustering of ovarian theca-interstitial cells. Molecular and Cellular Endocrinology 97(1-2): 37-49, 1993

NF-kappa B activation by tumor necrosis factor alpha in the Jurkat T cell line is independent of protein kinase A, protein kinase C, and Ca(2+)-regulated kinases. Cytokine 3(3): 257-265, 1991

MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase. Journal of Biological Chemistry 272(18): 12069-12075, 1997

Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. Journal of Biological Chemistry 278(44): 43603-43614, 2003

Nf kappa b activation by tumor necrosis factor alpha in the jurkat t cell line is independent of protein kinase a protein kinase c and calcium regulated kinases. Cytokine 3(3): 257-265, 1991

The death domain kinase RIP1 is essential for tumor necrosis factor alpha signaling to p38 mitogen-activated protein kinase. Molecular and Cellular Biology 23(22): 8377-8385, 2003

Lead increases lipopolysaccharide-induced liver-injury through tumor necrosis factor-alpha overexpression by monocytes/macrophages: role of protein kinase C and P42/44 mitogen-activated protein kinase. Environmental Health Perspectives 114(4): 507-513, 2006