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This Article Full Text Free Full Text (PDF) Free Supplemental Data All Versions of this Article: fj.08-113639v1 23/2/546    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Graham, J. D. Articles by Clarke, C. L. Search for Related Content PubMed PubMed Citation Articles by Graham, J. D. Articles by Clarke, C. L.

Nuclear matrix binding is critical for progesterone receptor movement into nuclear foci

J. Dinny Graham^*, Adrienne R. Hanson, Amanda J. Croft^*, Archa H. Fox and Christine L. Clarke^*,1

^* Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia; and

Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Perth, Western Australia, Australia

¹ Correspondence: Westmead Institute for Cancer Research, Westmead Millennium Institute, Darcy Rd., Westmead, NSW 2145, Australia. E-mail: christine_clarke{at}wmi.usyd.edu.au

The ovarian hormone progesterone is essential for normal breast development, and progesterone analogues are implicated in increasing breast cancer risk. The progesterone receptor (PR) is a transcription factor that, when ligand activated, moves rapidly into nuclear foci associated with transcriptional activity. However, the role of intranuclear trafficking signals in the focal location of PR is unknown. We have identified a mutation in PR that ablates its binding to the nuclear matrix and prevents PR movement into nuclear foci. Nuclear matrix binding mutants lack transcriptional activity and inhibit dimerization, demonstrating the critical role of matrix binding for PR dynamics and activity. DNA binding of PR is required for fidelity of location in foci, as DNA binding domain (DBD) mutants form aberrant foci with reduced mobility and altered tethering to the nucleus. Mutations in either the nuclear matrix targeting sequence or DBD domains were dominant in preventing wild-type receptor from moving to appropriate nuclear locations, demonstrating that both partner proteins in a PR dimer must have intact intranuclear trafficking signals for correct receptor positioning within the nucleus. This study has demonstrated that positioning of PR in foci within the nucleus is critically regulated by intranuclear trafficking signals, which play a key role in transcriptional activity and are relevant to its action in normal and malignant breast cells.—Graham, J. D., Hanson, A. R., Croft, A. C., Fox, A. H., Clarke, C. L. Nuclear matrix binding is critical for progesterone receptor movement into nuclear foci.

Key Words: intranuclear trafficking • breast cancer