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Meta-analysis of oncogenic protein kinase Ciota signaling in lung adenocarcinoma.

ABSTRACT: Atypical protein kinase Ciota (PKCiota) is an oncogene in non-small cell lung cancer (NSCLC). Here, we identify four functional gene targets of PKCiota in lung adenocarcinoma (LAC), the most prominent form of NSCLC.Three independent public domain gene expression data sets were interrogated to identify genes coordinately expressed with PKCiota in primary LAC tumors. Results were validated by QPCR in an independent set of primary LAC tumors. RNAi-mediated knockdown of PKCiota and the target genes was used to determine whether expression of the identified genes was regulated by PKCiota, and whether these target genes play a role in anchorage-independent growth and invasion of LAC cells.Meta-analysis identified seven genes whose expression correlated with PKCiota in primary LAC. Subsequent QPCR analysis confirmed coordinate overexpression of four genes (COPB2, ELF3, RFC4, and PLS1) in an independent set of LAC samples. RNAi-mediated knockdown showed that PKCiota regulates expression of all four genes in LAC cells, and that the four PKCiota target genes play an important role in the anchorage-independent growth and invasion of LAC cells. Meta-analysis of gene expression data sets from lung squamous cell, breast, colon, prostate, and pancreas carcinomas, as well as glioblastoma, revealed that a subset of PKCiota target genes, particularly COPB2 and RFC4, correlate with PKCiota expression in many tumor types.Meta-analysis of public gene expression data are useful in identifying novel gene targets of oncogenic PKCiota signaling. Our data indicate that both common and cell type-specific signaling mechanisms contribute to PKCiota-dependent transformation.

SUBMITTER: Erdogan E

PROVIDER: S-EPMC3260476 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Meta-analysis of oncogenic protein kinase Ciota signaling in lung adenocarcinoma.

Erdogan Eda E Klee Eric W EW Thompson E Aubrey EA Fields Alan P AP

Clinical cancer research : an official journal of the American Association for Cancer Research 20090217 5

<h4>Purpose</h4>Atypical protein kinase Ciota (PKCiota) is an oncogene in non-small cell lung cancer (NSCLC). Here, we identify four functional gene targets of PKCiota in lung adenocarcinoma (LAC), the most prominent form of NSCLC.<h4>Experimental design</h4>Three independent public domain gene expression data sets were interrogated to identify genes coordinately expressed with PKCiota in primary LAC tumors. Results were validated by QPCR in an independent set of primary LAC tumors. RNAi-mediate ...[more]

PMID: 19223491

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Project description:Ras recruits and activates effectors that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, Raf's activation requires dimerization, which can be facilitated by Ras dimerization. Previously, we showed that active K-Ras4B dimerizes in silico and in vitro through two major interfaces: (i) β-interface, mapped to Switch I and effector-binding regions, (ii) α-interface at the allosteric lobe. Here, we chose constitutively active K-Ras4B as our control and two double mutants (K101D and R102E; and R41E and K42D) in the α- and β-interfaces. Two of the mutations are from The Cancer Genome Atlas (TCGA) and the Catalogue Of Somatic Mutations In Cancer (COSMIC) data sets. R41 and R102 are found in several adenocarcinomas in Ras isoforms. We performed site-directed mutagenesis, cellular localization experiments, and molecular dynamics (MD) simulations to assess the impact of the mutations on K-Ras4B dimerization and function. α-interface K101D/R102E double mutations reduced dimerization but only slightly reduced downstream phosphorylated extracellular signal-regulated kinase (ERK) (pERK) levels. While β-interface R41E/K42D double mutations did not interfere with dimerization, they almost completely blocked K-Ras4B-mediated ERK phosphorylation. Both double mutations increased downstream phosphorylated Akt (pAkt) levels in cells. Changes in pERK and pAkt levels altered ERK- and Akt-regulated gene expressions, such as EGR1, JUN, and BCL2L11. These results underscore the role of the α-interface in K-Ras4B homodimerization and the β-surface in effector binding. MD simulations highlight that the membrane and hypervariable region (HVR) interact with both α- and β-interfaces of K-Ras4B mutants, respectively, inhibiting homodimerization and probably effector binding. Mutations at both interfaces interfered with mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase signaling but in different forms and extents. We conclude that dimerization is not necessary but enhances downstream MAPK signaling.

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Meta-analysis of oncogenic protein kinase Ciota signaling in lung adenocarcinoma.

Publications

Meta-analysis of oncogenic protein kinase Ciota signaling in lung adenocarcinoma.

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