Its Mechanism and Potential Role in Carcinogenesis

17.7% of cases and was associated with reduced expression levels. These results suggest that DUSP6 is a growth suppressor whose inactivation could promote the progression of lung cancer. We have here identified an important factor involved in carcinogenesis through a comprehensive search for downstream targets of oncogenic KRAS. (Am J Pathol 2009, 175:867–881; DOI: 10.2353/ajpath.2009.080489)

[1]  N. Wada,et al.  Prognostic value of KRAS mutations and Ki-67 expression in stage I lung adenocarcinomas. , 2009, Lung cancer.

[2]  G. Pagès,et al.  Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway , 2008, Oncogene.

[3]  S. Keyse,et al.  Dual-specificity MAP kinase phosphatases (MKPs) and cancer , 2008, Cancer and Metastasis Reviews.

[4]  R. Dickinson,et al.  Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter , 2008, The Biochemical journal.

[5]  T. Furukawa.  Molecular genetics of intraductal papillary-mucinous neoplasms of the pancreas. , 2007, Journal of hepato-biliary-pancreatic surgery.

[6]  S. Keyse,et al.  Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases , 2007, Oncogene.

[7]  M. Esteller.  Epigenetic gene silencing in cancer: the DNA hypermethylome. , 2007, Human molecular genetics.

[8]  Jeremy J. W. Chen,et al.  A five-gene signature and clinical outcome in non-small-cell lung cancer. , 2007, The New England journal of medicine.

[9]  Daryl A. Scott,et al.  Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development , 2007, Development.

[10]  K. Hamada,et al.  Growth regulation via insulin-like growth factor binding protein-4 and -2 in association with mutant K-ras in lung epithelia. , 2006, The American journal of pathology.

[11]  M. McDevitt,et al.  The HBP1 Transcriptional Repressor Participates in RAS-Induced Premature Senescence , 2006, Molecular and Cellular Biology.

[12]  J. Minna,et al.  Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells. , 2006, Cancer research.

[13]  A. Gazdar,et al.  Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers , 2006, International journal of cancer.

[14]  G. Speake,et al.  Recent developments related to the EGFR as a target for cancer chemotherapy. , 2005, Current opinion in pharmacology.

[15]  T. Furukawa,et al.  Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas , 2005, Modern Pathology.

[16]  T. Furukawa,et al.  Abrogation of DUSP6 by hypermethylation in human pancreatic cancer , 2005, Journal of Human Genetics.

[17]  Asif J. Chaudhry,et al.  Ras-Raf-Arf Signaling Critically Depends on the Dmp1 Transcription Factor , 2005, Molecular and Cellular Biology.

[18]  J. Pouysségur,et al.  Extracellular Signal-Regulated Kinases Phosphorylate Mitogen-Activated Protein Kinase Phosphatase 3/DUSP6 at Serines 159 and 197, Two Sites Critical for Its Proteasomal Degradation , 2005, Molecular and Cellular Biology.

[19]  E. Wattenberg,et al.  Mitogen-activated Protein Kinase Phosphatase-3 Is a Tumor Promoter Target in Initiated Cells That Express Oncogenic Ras* , 2004, Journal of Biological Chemistry.

[20]  R. DePinho,et al.  Telomeres, stem cells, senescence, and cancer. , 2004, The Journal of clinical investigation.

[21]  T. Kuriyama,et al.  NIH3T3 transfectant containing human K-ras oncogene shows enhanced metastatic activity after in vivo tumor growth or co-culture with fibroblasts , 1992, Clinical & Experimental Metastasis.

[22]  Takashi Takahashi,et al.  K-ras gene mutation enhances motility of immortalized airway cells and lung adenocarcinoma cells via Akt activation: possible contribution to non-invasive expansion of lung adenocarcinoma. , 2004, The American journal of pathology.

[23]  F. Motoi,et al.  Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. , 2003, The American journal of pathology.

[24]  G. Peters,et al.  Biallelic Mutations in p16INK4a Confer Resistance to Ras- and Ets-Induced Senescence in Human Diploid Fibroblasts , 2002, Molecular and Cellular Biology.

[25]  Eugenia Wang,et al.  Replicative senescence revisited. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[26]  E. Berg,et al.  World Health Organization Classification of Tumours , 2002 .

[27]  G. Peters,et al.  Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence , 2001, Nature.

[28]  Takaaki Ito,et al.  Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma. , 1999, American journal of clinical pathology.

[29]  E. Soeda,et al.  Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer , 1998, Cytogenetic and Genome Research.

[30]  R. Ward,et al.  Restriction endonuclease-mediated selective polymerase chain reaction: a novel assay for the detection of K-ras mutations in clinical samples. , 1998, The American journal of pathology.

[31]  A. Sharrocks,et al.  The Elk-1 ETS-Domain Transcription Factor Contains a Mitogen-Activated Protein Kinase Targeting Motif , 1998, Molecular and Cellular Biology.

[32]  Y. Yatabe,et al.  Establishment of human peripheral lung epithelial cell lines (HPL1) retaining differentiated characteristics and responsiveness to epidermal growth factor, hepatocyte growth factor, and transforming growth factor beta1. , 1997, Cancer research.

[33]  S. Lowe,et al.  Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a , 1997, Cell.

[34]  A. Ashworth,et al.  The Dual Specificity Phosphatases M3/6 and MKP-3 Are Highly Selective for Inactivation of Distinct Mitogen-activated Protein Kinases* , 1996, The Journal of Biological Chemistry.

[35]  M. Muda,et al.  MKP-3, a Novel Cytosolic Protein-tyrosine Phosphatase That Exemplifies a New Class of Mitogen-activated Protein Kinase Phosphatase (*) , 1996, The Journal of Biological Chemistry.

[36]  L. Chin,et al.  CFTR expression and chloride secretion in polarized immortal human bronchial epithelial cells. , 1994, American journal of respiratory cell and molecular biology.

[37]  Ananthaswamy Hn,et al.  Transformation of NIH3T3 cells by transfection with UV-irradiated human c-Ha-ras-1 proto-oncogene DNA. , 1991 .