Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival

2.50
Hdl Handle:
http://hdl.handle.net/10547/302099
Title:
Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival
Authors:
Lee, Ho-Young; Srinivas, Harish; Xia, Dianren; Lu, Yiling; Superty, Robert; LaPushin, Ruth; Gomez-Manzano, Candelaria; Gal, Annamaria; Walsh, Garrett L; Force, Thomas; Ueki, Kohjiro; Mills, Gordon B.; Kurie, Jonathan M.
Abstract:
Cancer cells in which the PTEN lipid phosphatase gene is deleted have constitutively activated phosphatidylinositol 3-kinase (PI3K)-dependent signaling and require activation of this pathway for survival. In non-small cell lung cancer (NSCLC) cells, PI3K-dependent signaling is typically activated through mechanisms other than PTEN gene loss. The role of PI3K in the survival of cancer cells that express wild-type PTEN has not been defined. Here we provide evidence that H1299 NSCLC cells, which express wild-type PTEN, underwent proliferative arrest following treatment with an inhibitor of all isoforms of class I PI3K catalytic activity (LY294002) or overexpression of the PTEN lipid phosphatase. In contrast, overexpression of a dominant-negative mutant of the p85alpha regulatory subunit of PI3K (Deltap85) induced apoptosis. Whereas PTEN and Delta85 both inhibited activation of AKT/protein kinase B, only Deltap85 inhibited c-Jun NH2-terminal kinase (JNK) activity. Cotransfection of the constitutively active mutant Rac-1 (Val12), an upstream activator of JNK, abrogated Deltap85-induced lung cancer cell death, whereas constitutively active mutant mitogen-activated protein kinase kinase (MKK)-1 (R4F) did not. Furthermore, LY294002 induced apoptosis of MKK4-null but not wild-type mouse embryo fibroblasts. Therefore, we propose that, in the setting of wild-type PTEN, PI3K- and MKK4/JNK-dependent pathways cooperate to maintain cell survival.
Affiliation:
University of Texas MD Anderson Cancer Center; New England Medical Center; Harvard Medical School
Citation:
Lee, H.Y., Srinivas, H., Xia, D., Lu, Y. (2003) 'Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival', The Journal of biological chemistry, 278(26),pp.23630-23638
Publisher:
American Society for Biochemistry and Molecular Biology
Journal:
The Journal of biological chemistry; Journal of biological chemistry
Issue Date:
27-Jun-2003
URI:
http://hdl.handle.net/10547/302099
DOI:
10.1074/jbc.M300997200
PubMed ID:
12714585
Additional Links:
http://www.ncbi.nlm.nih.gov/pubmed/12714585; http://www.jbc.org/content/278/26/23630.full
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
Cell and Cryobiology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorLee, Ho-Youngen_GB
dc.contributor.authorSrinivas, Harishen_GB
dc.contributor.authorXia, Dianrenen_GB
dc.contributor.authorLu, Yilingen_GB
dc.contributor.authorSuperty, Roberten_GB
dc.contributor.authorLaPushin, Ruthen_GB
dc.contributor.authorGomez-Manzano, Candelariaen_GB
dc.contributor.authorGal, Annamariaen_GB
dc.contributor.authorWalsh, Garrett Len_GB
dc.contributor.authorForce, Thomasen_GB
dc.contributor.authorUeki, Kohjiroen_GB
dc.contributor.authorMills, Gordon B.en_GB
dc.contributor.authorKurie, Jonathan M.en_GB
dc.date.accessioned2013-09-23T12:22:57Z-
dc.date.available2013-09-23T12:22:57Z-
dc.date.issued2003-06-27-
dc.identifier.citationLee, H.Y., Srinivas, H., Xia, D., Lu, Y. (2003) 'Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival', The Journal of biological chemistry, 278(26),pp.23630-23638en_GB
dc.identifier.issn0021-9258-
dc.identifier.pmid12714585-
dc.identifier.doi10.1074/jbc.M300997200-
dc.identifier.urihttp://hdl.handle.net/10547/302099-
dc.description.abstractCancer cells in which the PTEN lipid phosphatase gene is deleted have constitutively activated phosphatidylinositol 3-kinase (PI3K)-dependent signaling and require activation of this pathway for survival. In non-small cell lung cancer (NSCLC) cells, PI3K-dependent signaling is typically activated through mechanisms other than PTEN gene loss. The role of PI3K in the survival of cancer cells that express wild-type PTEN has not been defined. Here we provide evidence that H1299 NSCLC cells, which express wild-type PTEN, underwent proliferative arrest following treatment with an inhibitor of all isoforms of class I PI3K catalytic activity (LY294002) or overexpression of the PTEN lipid phosphatase. In contrast, overexpression of a dominant-negative mutant of the p85alpha regulatory subunit of PI3K (Deltap85) induced apoptosis. Whereas PTEN and Delta85 both inhibited activation of AKT/protein kinase B, only Deltap85 inhibited c-Jun NH2-terminal kinase (JNK) activity. Cotransfection of the constitutively active mutant Rac-1 (Val12), an upstream activator of JNK, abrogated Deltap85-induced lung cancer cell death, whereas constitutively active mutant mitogen-activated protein kinase kinase (MKK)-1 (R4F) did not. Furthermore, LY294002 induced apoptosis of MKK4-null but not wild-type mouse embryo fibroblasts. Therefore, we propose that, in the setting of wild-type PTEN, PI3K- and MKK4/JNK-dependent pathways cooperate to maintain cell survival.en_GB
dc.language.isoenen
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_GB
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/12714585en_GB
dc.relation.urlhttp://www.jbc.org/content/278/26/23630.fullen_GB
dc.rightsArchived with thanks to The Journal of biological chemistryen_GB
dc.subject.meshApoptosis-
dc.subject.meshCell Survival-
dc.subject.meshHumans-
dc.subject.meshJNK Mitogen-Activated Protein Kinases-
dc.subject.meshLung Neoplasms-
dc.subject.meshMAP Kinase Kinase 4-
dc.subject.meshMitogen-Activated Protein Kinase Kinases-
dc.subject.meshMitogen-Activated Protein Kinases-
dc.subject.meshMutation-
dc.subject.meshPTEN Phosphohydrolase-
dc.subject.meshPhosphatidylinositol 3-Kinases-
dc.subject.meshPhosphoric Monoester Hydrolases-
dc.subject.meshSignal Transduction-
dc.subject.meshTransfection-
dc.subject.meshTumor Cells, Cultured-
dc.subject.meshTumor Suppressor Proteins-
dc.titleEvidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survivalen
dc.typeArticleen
dc.contributor.departmentUniversity of Texas MD Anderson Cancer Centeren_GB
dc.contributor.departmentNew England Medical Centeren_GB
dc.contributor.departmentHarvard Medical Schoolen_GB
dc.identifier.journalThe Journal of biological chemistryen_GB
dc.identifier.journalJournal of biological chemistryen_GB

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