p53-mediated activation of miRNA34 candidate tumor-suppressor genes.
BACKGROUND
In response to varied cell stress signals, the p53 tumor-suppressor protein activates a multitude of genes encoding proteins with functions in cell-cycle control, DNA repair, senescence, and apoptosis. The role of p53 in transcription of other types of RNAs, such as microRNAs (miRNAs) is essentially unknown.


RESULTS
Using gene-expression analyses, reporter gene assays, and chromatin-immunoprecipitation approaches, we present definitive evidence that the abundance of the three-member miRNA34 family is directly regulated by p53 in cell lines and tissues. Using array-based approaches and algorithm predictions, we define genes likely to be directly regulated by miRNA34, with cell-cycle regulatory genes being the most prominent class. In addition, we provide functional evidence, obtained via antisense oligonucleotide transfection and the use of mouse embryonic stem cells with loss of miRNA34a function, that the BCL2 protein is regulated directly by miRNA34. Finally, we demonstrate that the expression of two miRNA34s is dramatically reduced in 6 of 14 (43%) non-small cell lung cancers (NSCLCs) and that the restoration of miRNA34 expression inhibits growth of NSCLC cells.


CONCLUSIONS
Taken together, the data suggest the miRNA34s might be key effectors of p53 tumor-suppressor function, and their inactivation might contribute to certain cancers.
Bommer
Guido T
GT
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109-2200, USA.
Gerin
Isabelle
I
Feng
Ying
Y
Kaczorowski
Andrew J
AJ
Kuick
Rork
R
Love
Robert E
RE
Zhai
Yali
Y
Giordano
Thomas J
TJ
Qin
Zhaohui S
ZS
Moore
Bethany B
BB
MacDougald
Ormond A
OA
Cho
Kathleen R
KR
Fearon
Eric R
ER
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53