An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation.
The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1- and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.
Talotta
F
F
Institute of Genetics and Biophysics A. Buzzati Traverso, CNR, Naples, Italy.
Cimmino
A
A
Matarazzo
M R
MR
Casalino
L
L
De Vita
G
G
D'Esposito
M
M
Di Lauro
R
R
Verde
P
P
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
D051017:Apoptosis Regulatory Proteins; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D018631:ras Proteins; D000099169:Fos-Related Antigen 1; C524940:MIRN21 microRNA, human; C467042:Pdcd4 protein, rat