The nucleocrine pathway comes of age

More than 20 years ago, it was initially predicted that hormones and growth factors might promote cell growth by binding and thereby inactivating tumor suppressors, as exemplified by the proposed complex formation between insulin and retinoblastoma protein (RB). This mainly intracellular/nuclear growth-regulatory circuit was termed "the nucleocrine pathway" and the physical interaction between insulin and RB was subsequently proven through several methods, primarily by immunofluorescence and co-immunoprecipitation. Meanwhile, additional nucleocrine pairs have emerged through further experimental studies, specifically the FGF1-p53 and angiogenin-p53 heterodimers. Moreover, first experimental clues have been obtained as to the intranuclear presence of the previously surmised heterodimer between the EGF precursor and the p130 tumor suppressor. In addition, RB-binding motifs have recently been discovered in interleukin-6 (IL-6) and cellular apoptosis susceptibility (CAS) protein. These findings point to a more general significance of the nucleocrine pathway in cell growth regulation and as a particularly useful target in cancer therapy.