Because of the association between aberrant nuclear structure and tumour grade, nuclear morphology is an indispensible criterion in the current pathological assessment of cancer. Components of the nuclear envelope environment have central roles in many aspects of cell function that affect tumour development and progression. As the roles of the nuclear envelope components, including nuclear pore complexes and nuclear lamina, are being deciphered in molecular detail there are opportunities to harness this knowledge for cancer therapeutics and biomarker development. In this Review, we summarize the progress that has been made in our understanding of the nuclear envelope and the implications of changes in this environment for cancer biology.

Cyclosporin A and FK506 are immunosuppressive compounds that have similar inhibitory effects on the expression of several lymphokines produced by T lymphocytes. Despite their similar effects the drugs bind to two different cytosolic protein, cyclophilin and FKBP respectively, which raises the possibility that they have different modes of action. Using constructs in which mRNA production controlled by a specific transcription factor could be readily measured we found that both cyclosporin A and FK506 completely inhibited transcription activated by NF‐AT, NFIL2 A, NFIL2 B and partially inhibited transcription activated by NF kappa B. Cyclosporin A and FK506 inhibited only transcriptional activation that was dependent on Ca2+ mobilization. However, cyclosporin A and FK506 did not inhibit Ca2+ mobilization dependent expression of c‐fos mRNA indicating that only a subset of signalling pathways regulated by Ca2+ is sensitive to these drugs. Furthermore, we did not observe any qualitative differences between the effect of cyclosporin A and FK506 on six different transcription factors which suggests that these drugs may interfere with the activity of a novel Ca2+ dependent step that regulates several transcription factors.

The important conclusion is that the import receptors and Douglass J. Forbes for a number of the major nuclear localization pathways Department of Biology 0347 are becoming known (Figure 2, top). It is the clear expec-University of California at San Diego tation that additional receptors for other import path-La Jolla, California 92093 ways will also be found. Nuclear ExportRNAs exit the nucleus through the nuclear pore. Elegant

SignificanceThe molecular mechanism for sealing newly formed nuclear envelopes was unclear until the recent discovery that endosomal sorting complexes required for transport III (ESCRT-III) proteins mediate this process. Cmp7p (CHMP7), in particular, was identified as an early acting factor that recruits other ESCRT-III proteins to the nuclear envelope. A fundamental aspect of the varied roles of ESCRT factors is their recruitment by site-specific adaptors, yet the central question of how the ESCRT machinery is targeted to nuclear membranes has remained outstanding. Our study identifies the inner nuclear membrane protein LEM2 as a key, conserved factor that recruits CHMP7 and downstream ESCRT-III proteins to breaches in the nuclear envelope.