Nuclear ras: Unexpected subcellular distribution of oncogenic forms

The Harvey-ras gene encodes small guanine nucleotide binding proteins, muta nt 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 po st-translational processing of Ras is essential for cytoplasmic membrane lo calization and function. Surprisingly, irnmunofluorescence analysis provide d evidence that in addition to its cytosolic localization, activated H-Ras( Val) (12) was also localized in the nuclei of transformed cells both in vit ro and in vivo. Immunoblot analysis of nuclear fractions was consistent wit h results found by immunohistochemistry. Moreover, inhibition of protein fa rnesylation prevented the nuclear targeting of activated H-Ras(Val) (12) an d NF kappaB. Alterations in subcellular distribution pattern and phosphoryl ation of the cell cycle inhibitor p27, which is involved in Ras driven tumo r growth, coincided with nuclear localization of H-Ras(Val) (12). Proteins are often not functional until they are transported to their final destinat ion. indeed, Ras was found to complex with NTF2 a factor involved in nuclea r protein import and export. Therefore it is suggested that NTF2 is the act ual carrier for oncogenic Ras. In view of these observations the question a rises whether the nuclear localization of H-Ras(Val) (12) in tumors is impo rtant in oncogenic activation or whether it is a response to apoptosis. (C) 2001 Wiley-Liss Inc.