MKK4 as oncogene or tumor supressor: In cancer and senescence, the story's getting old

MKK4 gene is selected against by inactivating mutations in a large number of different tumor types, eg, tumors of the pancreas, bile ducts, breast, colon, lungs, testes [1-3] at a remarkably consistent rate of approximately 5-10% of tumors, identifying and defining it, therefore, as a tumor-suppressor (or genome-maintenance) gene [4]. Yet, experimental evidence exists that supports a pro-oncogenic role for MKK4 [5, 6]. Finegan and Tournier [6], for example, recently used an inducible murine model of MKK4 homozygous deletion to evaluate the role of MKK4 in skin tumorigenesis. They found that skin-specific MKK4-null mice were resistant to carcinogen-induced tumorigenesis. While the paper is well written and the model well designed, the fundamental premise may well be flawed, especially concerning MKK4's role in tumorigenesis, perhaps misleading the line of experimentation. There should be no question that MKK4 is tumor-suppressive, not oncogenic. MKK4 is widely selected against by tumors (its low rate of homozygous loss may be accounted for by a higher rate of heterozygous loss that could rationalize frequent 17p loss in diverse human cancers[7]) and unsurprisingly patients whose tumors have loss of MKK4 show statistically significant decrease in survival in the best controlled studies, using calibrated immunohistochemistry in large numbers of patients [8], consistent with a tumor-suppressive role. Similarly consistent with a growth-suppressive role of MKK4 are observations made regarding the relationship between MKK4 and senescence. One of the ways MKK4 may suppress tumors is by inhibiting cell proliferation during replicative senescence, a widely re-Commentary cognized mechanism of tumor suppression. Marasa et al. [9] recently observed that MKK4 abundance increases in senescent fibroblasts. Overexpression of MKK4 decreased proliferation and promoted a senescent phenotype in young WI-38 human diploid fibroblasts and conversely, when MKK4 levels were lowered by several microRNAs targeting the MKK4 mRNA, the senescent phenotype was ameliorated and cells proliferated more rapidly [9]. In keeping with these observations, human tissue from older individuals was observed to express higher levels of MKK4 than corresponding tissue from young donors [9]. In the discussion of their inducible murine model of MKK4 homozygous deletion, Finegan and Tournier [6] rightly point out that there is conflicting literature regarding MKK4's role in tumorigenesis. The reason for the conflicting literature is largely because MKK4 is difficult to study experimentally. Their model would not be the first homozygous deletion model to model a population or a phenomenon that was not anticipated. For example, our own studies using …