Phosphorylation and Activation of Cell Division Cycle Associated 5 by Mitogen-Activated Protein Kinase Play a Crucial Role in Human Lung Carcinogenesis

Abstract

We analyzed the gene expression profiles of clinical lung carcinomas using a cDNA microarray containing 27,648 genes or expressed sequence tags, and identified CDCA5 (cell division cycle associated 5) to be upregulated in the majority of lung cancers. Tumor tissue microarray analysis of 262 non-small cell lung cancer patients revealed that CDCA5 positivity was an independent prognostic factor for lung cancer patients. Suppression of CDCA5 expression with siRNAs inhibited the growth of lung cancer cells; concordantly, induction of exogenous expression of CDCA5 conferred growth-promoting activity in mammalian cells. We also found that extracellular signal-regulated kinase (ERK) kinase phosphorylated CDCA5 at Ser79 and Ser209 in vivo. Exogenous expression of phospho-mimicking CDCA5 protein whose Ser209 residue was replaced with glutamine acid further enhanced the growth of cancer cells. In addition, functional inhibition of the interaction between CDCA5 and ERK kinase by a cell-permeable peptide corresponding to a 20-amino-acid sequence part of CDCA5, which included the Ser209 phosphorylation site by ERK, significantly reduced phosphorylation of CDCA5 and resulted in growth suppression of lung cancer cells. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy.Cancer Res; 70(13); 5337-47. ©2010 AACR.

Sororin is a master regulator of sister chromatid cohesion and separation

“…Immunohistochemical analysis of 262 non-small cell lung cancer samples shows that more than 70% of these cases are Sororinpositive, and Sororin positivity is significantly associated with poor prognosis (p < 0.05). 39 heterodimer without the presence of chromatin and Sororin with mutations in the FGF motif is less efficient in displacing Wapl. However, when recombinant Sororin was added to Xenopus egg extracts containing chromatin, rather than being decreased, the level of Wapl on chromatin increased, 12 suggesting that Sororin may play a role in stabilizing Pds5-Wapl and cohesin, rather than displacing Wapl from cohesin.…”

“…To date, only two kinases (Cdk1/cyclin B and ERK2) have been verified to phosphorylate Sororin. 20,21,39 The minimum consensus sequence for Cdk1/cyclin B phosphorylation is (S/T)P and the full consensus sequence is (S/T)Px(K/R). [40][41][42] There are six putative minimum consensus sequences (T, 48 , all the other eight sites have been confirmed by mass spectrometry using in vitro Cdk1/cyclin B assay ( Table 1).…”

“…39 In in vitro assays, Sororin is phosphorylated by Plk1, but the phosphorylation sites remain to be identified. 20 The role of…”

Identification of Epstein-Barr Virus–Induced Gene 3 as a Novel Serum and Tissue Biomarker and a Therapeutic Target for Lung Cancer

“…[6][7][8][9][10]. To verify the biological and clinicopathologic significance of the respective gene products, we carried out tumor tissue microarray analysis of clinical lung cancer materials as well as loss of function assays, using siRNA (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). We also used ELISA to determine whether the genes exhibiting a tumor-specific transmembrane/secretory protein are potential diagnostic serum biomarkers (30)(31)(32)(33)(34)(35).…”

RASEF is a Novel Diagnostic Biomarker and a Therapeutic Target for Lung Cancer

“…To further investigate the biologic importance of the interaction between RASEF and ERK1/2 that had been confirmed by above-mentioned assays in lung cancer cell growth, the 3 different 23-amino-acid polypeptides covering the ERK1/2-interacting site on RASEF 520-575 with a membrane-permeable 11 residues of arginine (11R) at its Nterminus (11R-RASEF 520-542, RRRRRRRRRRR-GGG-SALSPQTDLVDDNAKSFSSQKAY; 11R-RASEF 536-558, RRRRRRRRRRR-GGG-FSSQKAYKIVLAGDAAV-GKSSFL; 11R-RASEF 553-575, RRRRRRRRRRR-GGG-GKSSFLMRLCKNEFRENISATLG) were synthesized as previously described (17,20,28,29). Scramble peptides (SCR) derived from the 11R-RASEF 553 to 575 peptides that showed growth suppressive effect on cancer cells were synthesized as a control (RRRRRRRRRRR-GGG-RSEN-KMSLFRGSEFTLLKGCINA).…”