Nuclear Ras: Unexpected subcellular distribution of oncogenic forms

The Harvey-ras gene encodes small guanine nucleotide binding proteins, mutant forms of which are associated with a number of human malignancies. Based on studies with truncated forms of the protein it is known that correct post-translational processing of Ras is essential for cytoplasmic membrane localization and function. Surprisingly, immunofluorescence analysis provided evidence that in addition to its cytosolic localization, activated H-RasVal 12 was also localized in the nuclei of transformed cells both in vitro and in vivo. Immunoblot analysis of nuclear fractions was consistent with results found by immunohistochemistry. Moreover, inhibition of protein farnesylation prevented the nuclear targeting of activated H-RasVal 12 and NFκB. Alterations in subcellular distribution pattern and phosphorylation of the cell cycle inhibitor p27, which is involved in Ras driven tumor growth, coincided with nuclear localization of H-RasVal 12. Proteins are often not functional until they are transported to their final destination. Indeed, Ras was found to complex with NTF2 a factor involved in nuclear protein import and export. Therefore it is suggested that NTF2 is the actual carrier for oncogenic Ras. In view of these observations the question arises whether the nuclear localization of H-RasVal 12 in tumors is important in oncogenic activation or whether it is a response to apoptosis. J. Cell. Biochem. Suppl. 36: 1-11, 2001. © 2001 Wiley-Liss. Inc.