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In 1994, I conjectured that insulin-degrading enzyme (IDE) acts as aninhibitor of malignant transformation by degrading insulin and thus preventingthis major growth-stimulatory hormone from binding and thereby inactivating theretinoblastoma tumor suppressor protein (RB). Ten years later, I discoveredthat a carboxyterminal RB amino acid sequence resembles the catalytic center ofIDE. This structural homology raised the possibility that insulin degradationis a basic mechanism for tumor suppression shared by RB and IDE. Subsequently,a first immunohistochemical study on the differential expression of human IDEin normal tissues, primary tumors and their corresponding lymph node metastasesfurther corroborated the initial conjecture on IDE being an antineoplasticmolecule. In this report, it is shown that IDE harbors ankyrin repeat-likeamino acid sequences through which it might bind and, as a result, antagonizethe pro-inflammatory factor NF-kappaB as well as cyclin-dependent kinases(CDKs). As equally revealed here, IDE also contains 2 RXL cyclin-binding motifswhich could contribute to its presumed inhibition of CDKs. These new findingssuggest that IDE is potentially able to suppress both inflammation andoncogenesis by several mechanisms that ultimately ensure RB function.

Tumor suppressor and anti-inflammatory protein: an expanded view on insulin-degrading enzyme (IDE)