Subnuclear targeting of the Runx3 tumor suppressor and its epigenetic association with mitotic chromosomes.
Runx proteins are tissue-specific transcriptional scaffolds that organize and assemble regulatory complexes at strategic sites of target gene promoters and at intranuclear foci to govern activation or repression. During interphase, fidelity of intranuclear targeting supports the biological activity of Runx1 and Runx2 proteins. Both factors regulate genes involved in cell cycle control and cell growth (e.g., rRNA genes), as well as lineage commitment. Here, we have examined the subcellular regulatory properties of the third Runx member, the tumor suppressor protein Runx3, during interphase and mitosis. Using in situ cellular and biochemical approaches we delineated a subnuclear targeting signal that directs Runx3 to discrete transcriptional foci that are nuclear matrix associated. Chromatin immunoprecipitation results show that Runx3 occupies rRNA promoters during interphase. We also find that Runx3 remains associated with chromosomes during mitosis and localizes with nucleolar organizing regions (NORs), reflecting an interaction with epigenetic potential. Taken together, our study establishes that common mechanisms control the subnuclear distribution and activities of Runx1, Runx2, and Runx3 proteins to support RNA polymerase I and II mediated gene expression during interphase and mitosis.
Pande
Sandhya
S
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Ali
Syed A
SA
Dowdy
Christopher
C
Zaidi
Sayyed K
SK
Ito
Kosei
K
Ito
Yoshiaki
Y
Montecino
Martin A
MA
Lian
Jane B
JB
Stein
Janet L
JL
van Wijnen
Andre J
AJ
Stein
Gary S
GS
D000818:Animals; D002875:Chromosomes / Q000378:metabolism*; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006367:HeLa Cells; D006801:Humans; D007399:Interphase; D008938:Mitosis; D019913:Nuclear Localization Signals; D015530:Nuclear Matrix / Q000378:metabolism; D009697:Nucleolus Organizer Region / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D012335:RNA, Ribosomal / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D050677:Core Binding Factor Alpha 3 Subunit; D019913:Nuclear Localization Signals; D012335:RNA, Ribosomal; D025521:Tumor Suppressor Proteins