MKK2 is sufficient but not necessary for proliferation and anchorage-independent growth of SK-MEL-28 cells.

ABSTRACT: Though mitogen activated protein kinase kinases (MKK or MEK) 1 and 2 are widely assumed to be functionally redundant some reports indicate they possess distinct biologic activities. To test the hypothesis that MEK1 and MEK2 signaling pathways are interchangeable we used two complementary approaches to determine the necessity and sufficiency of individual MEK1 and MEK2 signaling pathways for human melanoma SK-MEL-28 cell proliferation. To test the necessity we targeted MEK1 and/or MEK2 using specific siRNAs. An effect on proliferation was observed only when both MEK1 and MEK2 were knocked down indicating that neither of the individual MEK isoforms is necessary for SK-MEL-28 cell proliferation. To test the sufficiency we inhibited multiple MEK and MKK signaling pathways in SK-MEL-28 cells with anthrax lethal toxin (LeTx) a MEK/MKK-specific protease and rescued individual MEK signaling pathways by expressing a cleavage-resistant form of MEK (MEKcr). In this fashion ERK activation was retained only in MEK2cr-expressing cells but not in MEK1cr-expressing cells following LeTx treatment. Microarray analysis revealed groups of non-overlapping downstream transcriptional targets of MEK1 and MEK2 and indicated a substantial rescue effect of MEK2cr on proliferation pathways. Furthermore LeTx efficiently inhibited the cell proliferation and anchorage-independent growth of SK-MEL-28 cells expressing MKK1cr but not MEK2cr. These results not only indicate that in this cellular context MEK2 signaling pathway alone is sufficient for ERK activation melanoma cell proliferation and anchorage-independent growth but MEK1 is not but also demonstrate that MEK1 and MEK2 signaling pathways are not redundant and interchangeable for melanoma cell proliferation. We conclude that while MEK2 alone is sufficient for SK-MEL-28 cell proliferation MEK1 can conditionally compensate for loss of MEK2. SK-MEL-28 melanoma cells +/- cleavage resistant MKK1/MKK2

ORGANISM(S): Homo sapiens

SUBMITTER: Karl Dykema 

PROVIDER: E-GEOD-23930 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress