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Oncogene. 2015 Apr 30;34(18):2337-46. doi: 10.1038/onc.2014.182. Epub 2014 Jul 7.

A novel LKB1 isoform enhances AMPK metabolic activity and displays oncogenic properties.

Author information

1
1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France.
2
Institut Albert Bonniot, CRI Inserm/UJF U823, Rond Point de la Chantourne, La Tronche, France.
3
1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France.
4
Section of Cardiology, Boston University School of Medicine, Boston, MA, USA.
5
1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France [5] Pathology Unit, Hôpital Cochin, Paris, France.

Abstract

The LKB1 tumor suppressor gene encodes a master kinase that coordinates the regulation of energetic metabolism and cell polarity. We now report the identification of a novel isoform of LKB1 (named ΔN-LKB1) that is generated through alternative transcription and internal initiation of translation of the LKB1 mRNA. The ΔN-LKB1 protein lacks the N-terminal region and a portion of the kinase domain. Although ΔN-LKB1 is catalytically inactive, it potentiates the stimulating effect of LKB1 on the AMP-activated protein kinase (AMPK) metabolic sensor through a direct interaction with the regulatory autoinhibitory domain of AMPK. In contrast, ΔN-LKB1 negatively interferes with the LKB1 polarizing activity. Finally, combining in vitro and in vivo approaches, we showed that ΔN-LKB1 has an intrinsic oncogenic property. ΔN-LKB1 is expressed solely in the lung cancer cell line, NCI-H460. Silencing of ΔN-LKB1 decreased the survival of NCI-H460 cells and inhibited their tumorigenicity when engrafted in nude mice. In conclusion, we have identified a novel LKB1 isoform that enhances the LKB1-controlled AMPK metabolic activity but inhibits LKB1-induced polarizing activity. Both the LKB1 tumor suppressor gene and the oncogene ΔN-LKB1 are expressed from the same locus and this may account for some of the paradoxical effects of LKB1 during tumorigenesis.

PMID:
24998845
DOI:
10.1038/onc.2014.182
[Indexed for MEDLINE]

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