E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis.
E2F1 is a positive regulator of cell cycle progression and also a potent inducer of apoptosis, especially when activated by DNA damage. We identified E2F1-inducible microRNAs (miRNAs) by microarray hybridization and found that the levels of miRNAs 449a and 449b, as well as their host gene CDC20B, are strongly upregulated by E2F1. High miR-449 levels were found in testes, lung, and trachea, but not in testicular and other cancer cells. MiR-449a/b structurally resemble the p53-inducible miRNA 34 family. In agreement with a putative tumor-suppressive role, miR-449a as well as miR-34a reduced proliferation and strongly promoted apoptosis by at least partially p53-independent mechanisms. Both miRNAs reduced the levels of CDK6, implying miR-449 in a negative feedback mechanism for E2F1. Moreover, miR-449a and miR-34a diminished the deacetylase Sirt1 and augmented p53 acetylation. We propose that both miRNAs provide a twofold safety mechanism to avoid excessive E2F1-induced proliferation by cell cycle arrest and by apoptosis. While responding to different transactivators, miRNAs 449 and 34 each repress E2F1, but promote p53 activity, allowing efficient cross-talk between two major DNA damage-responsive gene regulators.
Lizé
M
M
Department of Molecular Oncology, Göttingen Center of Molecular Biosciences -GZMB, Ernst Caspari Haus, University of Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany.
Pilarski
S
S
Dobbelstein
M
M
D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism
D050687:E2F1 Transcription Factor; C522425:MIRN34 microRNA, human; C544530:MIRN449 microRNA, human; D035683:MicroRNAs; D051361:Cyclin-Dependent Kinase 6; D037761:Sirtuins