Type

Journal Article

Authors

Raymond L Stallings
Derek M Murphy
Karen M Watters
Kenneth Bryan
Maria Meehan
Joanna Fay
Jennifer Lynch

Subjects

Biochemistry

Topics
transcription factors neoplasm invasiveness phosphorylation oncogene proteins antagonists inhibitors rock1 protein human protein processing post translational rho associated kinases humans metabolism mirn335 microrna human myosin light chains nuclear proteins glycoproteins down regulation micrornas signal transduction mycn protein human genetics cell line tumor up regulation disease progression mitogen activated protein kinase 1 cell movement pathology lrg1 protein human neuroblastoma transforming growth factor beta mapk1 protein human

MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-β signalling pathway. (2012)

Abstract Transforming growth factor-β (TGF-β) signaling regulates many diverse cellular activities through both canonical (SMAD-dependent) and non-canonical branches, which includes the mitogen-activated protein kinase (MAPK), Rho-like guanosine triphosphatase and phosphatidylinositol-3-kinase/AKT pathways. Here, we demonstrate that miR-335 directly targets and downregulates genes in the TGF-β non-canonical pathways, including the Rho-associated coiled-coil containing protein (ROCK1) and MAPK1, resulting in reduced phosphorylation of downstream pathway members. Specifically, inhibition of ROCK1 and MAPK1 reduces phosphorylation levels of the motor protein myosin light chain (MLC) leading to a significant inhibition of the invasive and migratory potential of neuroblastoma cells. Additionally, miR-335 targets the leucine-rich alpha-2-glycoprotein 1 (LRG1) messenger RNA, which similarly results in a significant reduction in the phosphorylation status of MLC and a decrease in neuroblastoma cell migration and invasion. Thus, we link LRG1 to the migratory machinery of the cell, altering its activity presumably by exerting its effect within the non-canonical TGF-β pathway. Moreover, we demonstrate that the MYCN transcription factor, whose coding sequence is highly amplified in a particularly clinically aggressive neuroblastoma tumor subtype, directly binds to a region immediately upstream of the miR-335 transcriptional start site, resulting in transcriptional repression. We conclude that MYCN contributes to neuroblastoma cell migration and invasion, by directly downregulating miR-335, resulting in the upregulation of the TGF-β signaling pathway members ROCK1, MAPK1 and putative member LRG1, which positively promote this process. Our results provide novel insight into the direct regulation of TGF-β non-canonical signaling by miR-335, which in turn is downregulated by MYCN.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Raymond L Stallings, Derek M Murphy, Karen M Watters, Kenneth Bryan, Maria Meehan, Joanna Fay, Jennifer Lynch

Experts in our system

1
Raymond L Stallings
Royal College of Surgeons in Ireland
Total Publications: 59
 
2
Kenneth Bryan
Royal College of Surgeons in Ireland
Total Publications: 36
 
3
Joanna Fay
Royal College of Surgeons in Ireland
Total Publications: 24