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The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression
02/13/2011
Figure. MKK7 controls KRasG12D-driven lung and NeuT-driven breast tumorigenesis through p53 expression. A, Representative H&E stainings showing accelerated progression and increased tumor burden in KRas;Map2k7fl/Δ mice. B, Representative histology of mammary cancers that developed in 16 week old NeuT;Map2k7Δ/mam and NeuT;Map2k7Δmam littermate females. H&E stained sections are shown. C and D, Western blot analysis for p53 and MKK7 levels in KRasG12D-driven lung (C) and NeuT-driven breast tumors (D). β-actin is shown as loading control.
This study seeks to define the molecular regulation of epithelial cells during the early steps of cellular transformation using primary cell culture and genetic ablation studies. We have focused on a signaling molecule with hitherto ill-defined functions during tumorigenesis: MKK7 and its downstream factors JNK1 and JNK2. This signaling cascade serves as an intracellular messenger receiving and allocating various cellular stimuli such as stress signals and inflammatory cues.
We could now show that MKK7 and the JNK signaling pathway also functions to suppress tumor formation in various organs such as the lung, the breast and the skin. It is well know that cells generally counteract oncogenic transformation by activating a cellular fail-safe mechanism: p53-induced cell cycle arrest or cellular suicide. This mechanism is absolutely crucial considering the trillions of cells in our body susceptible to sporadic mutations, which could ignite uncontrolled proliferation and tumor development. Failure of this mechanism leads to development of multiple, spontaneous tumors in humans and in mice. Using knock-out mice and improved primary cell culture systems I could show that MKK7 directly couples oncogenic and genotoxic stress to p53 stability required for cell cycle arrest and suppression of NeuT-induced breast and KRasG12D-induced lung tumors (Figure 1). Importantly, p53 overexpression could revert lung tumorigenesis in MKK7-deficient animals unambiguously confirming this new tumor suppressive mechanism. This study identified MKK7 as a vital molecular sensor to set a cellular anti-cancer barrier by linking oncogenic stress and the DNA damage response (DDR) to the key tumor suppressor p53. This work was recently featured as an Article in Nature Genetics.
>>link to article on Nature Genetics website
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