Theoretical Proposal: Allele Dosage of MAP2K4/MKK4 Could Rationalize Frequent 17p Loss in Diverse Human Cancers

Abstract

Although aneuploidy is a global genomic abnormality present in most humancancers, the clonal selection model best explains the action of select activating mutations inoncogenes and homozygous losses of tumor-suppressor genes. Simple gene dosage changesare difficult however, to incorporate into this model, in part due to negative feedback loopsthat govern major cancer mutational targets (eg, TP53, PTCH, SMAD4) and essentiallypreclude a haploinsufficient phenotype. The 17p conundrum may offer a clue to reconcilingthis difficulty: In comparison to the moderate mutation rate of TP53, many tumors have adisproportionately high frequency of loss of 17p. This discrepancy, and similarlydiscrepancies at other sites of LOH, has long been thought to be due to the presence ofundiscovered yet frequently mutated tumor-suppressor genes. However, over 15 years ofsearching for this grail has distributed bountiful disappointment. It is perhaps time toseriously consider an alternative explanation. Located on 17p adjacent to the TP53 gene,MKK4 is one of the most consistently mutated genes across tumor types, and is located onone of the most frequently lost arms in the human genome. We theorized that a gene dosagedependentphenotype of MKK4 could plausibly promote the emergence of 17p LOH andthereby the probability of evolving the biallelic inactivation of TP53. Using MKK4 somatichuman knockout cancer cells, we observed the proof-of-principle in the downstream genedosage-dependent phenotypes: heterozygous and homozygous knockouts were progressivelydeficient in Mkk4 protein, in stress-induced phosphorylation of Jnk, and the resultant upregulationof JUN mRNA. These observations highlight a lack of compensatory regulationwhen gene dosage changes perturb the Jnk-Jun relationship. Consideration of gene dosagechanges specifically affecting members of positive feedback loops may permit integration ofthe aneuploidy process into a conventional model of clonal selection in tumorigenesis.