Cyclin D1 blocks the anti-proliferative function of RUNX3 by interfering with RUNX3-p300 interaction.
Transcriptional function of cyclin D1, whose deregulation is frequently observed in human cancers, has been suggested to contribute to cancer formation. In the present study, we show that cyclin D1 protein inhibits RUNX3 activity by directly binding to it and interfering with its interaction with p300 interaction in lung cancer cells. Cyclin D1 inhibits p300-dependent RUNX3 acetylation and negatively regulates cyclin-dependent kinase (cdk) inhibitor p21 expression. These transcriptional effects of cyclin D1 do not require cdk4/6 kinase activation. We propose that cyclin D1 provides a transcriptional switch that allows the tumor suppressor activity of RUNX3 to be repressed in cancer cells. Since RUNX3 plays tumor suppressive roles in a wide range of cancers, a non-canonical cyclin D1 function may be critical for neoplastic transformation of the epithelial cells in which RUNX3 regulates proliferation.
Iwatani
Kazunori
K
Division of Pathology and Experimental Medicine, Graduate School of Life Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto-shi 861-8556, Japan.
Fujimoto
Tetsuhiro
T
Ito
Takaaki
T
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
D050677:Core Binding Factor Alpha 3 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; C493729:Runx3 protein, human; D019938:Cyclin D1; D050880:p300-CBP Transcription Factors