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