Dataset Information


Transcriptional profiling of MKK4-depleted cells

ABSTRACT: Mitogen-activated protein kinase kinase 4 (MKK4) is a dual-specificity kinase activated by environmental stress, cytokines, and peptide growth factors that reportedly can promote or inhibit tumor cell growth and metastasis. Somatic mutations in the gene encoding MKK4 (MAP2K4) have been identified in various human cancers, but the consequences of these mutations on MKK4 function and the biology of tumor cells that have them have not been elucidated. Here we report that, of the eleven mutations within the MAP2K kinase domain described thus far, one had gain-of-function (Q142L) and six had loss-of-function. Three of the loss-of-function mutations are nonsense mutations that produced C-terminally-truncated proteins (I295fs*23, R304*, and W310*) that were highly ubiqitinated and rapidly degraded when introduced into cells, and three are missense mutations in the ATP-binding pocket (N234I), activation loop (S251N), or C-lobe (P326L). We modeled the consequences of MAP2K4 loss-of-function mutations on cells by introducing MKK4 short-hairpin RNA constructs and found that MKK4 depletion enhanced the ability of a weakly tumorigenic murine cancer cell to metastasize when injected into syngeneic mice but had no effect on primary tumor formation. MKK4-depleted cells exhibited an increased capacity to migrate across PET filters and to invade through matrigel but no change in anchorage-dependent or -independent proliferation. Transcriptional profiling of these cells revealed gene expression changes that promote epithelial-to-mesenchymal transition and angiogenesis. We conclude that MKK4 inactivation promoted metastasis but not primary tumor formation. Collectively, these findings implicate loss-of-function MAP2K4 somatic mutations in tumor metastasis and provide one of the few examples of a somatic mutation in cancer cells that exerts a metastasis-specific effect. Keywords: Two-group comparison. 393P cells were infected with retroviruses expressing a MKK4-specific shRNA construct (shZ) or scrambled control (scr). 393P-shZ and 393P-scr were transcriptionally profiled in triplicate cultures.

ORGANISM(S): Mus musculus  

SUBMITTER: Chad Creighton   Wei Lin  Jon Kurie  Don Gibbons  Young-Ho Ahn 

PROVIDER: E-GEOD-19091 | ArrayExpress | 2011-09-30



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Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor γ2 expression.

Ahn Young-Ho YH   Yang Yanan Y   Gibbons Don L DL   Creighton Chad J CJ   Yang Fei F   Wistuba Ignacio I II   Lin Wei W   Thilaganathan Nishan N   Alvarez Cristina A CA   Roybal Jonathon J   Goldsmith Elizabeth J EJ   Tournier Cathy C   Kurie Jonathan M JM  

Molecular and cellular biology 20110906 21

MAP2K4 encodes a dual-specificity kinase (mitogen-activated protein kinase kinase 4, or MKK4) that is mutated in a variety of human malignancies, but the biochemical properties of the mutant kinases and their roles in tumorigenesis have not been fully elucidated. Here we showed that 8 out of 11 cancer-associated MAP2K4 mutations reduce MKK4 protein stability or impair its kinase activity. On the basis of findings from bioinformatic studies on human cancer cell lines with homozygous MAP2K4 loss,  ...[more]

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