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.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Neoplasms, Experimental/metabolism , Protein Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinase Kinases , Alternative Splicing , Animals , Catalytic Domain , Cell Line, Tumor , Humans , Isoenzymes/chemistry , Isoenzymes/metabolism , Mice , Mice, Nude , Muscle, Skeletal/metabolism , Myocardium/metabolism , Neoplasm Transplantation , Neoplasms, Experimental/pathology , Protein Serine-Threonine Kinases/chemistryABSTRACT
A large range of immunological investigations in patients with extrinsic or intrinsic asthma showed higher leucocyte counts in intrinsic asthma. Blood sputum eosinophilia were almost equally frequent. Immediate skin responses to inhalant antigens are seldom present in intrinsic asthma, but delayed responses to bacterial antigens, endotoxins, Candida albicans ans aspiryl-PPL are frequently positive. This correlates with the frequent presence of precipitins and in vitro stimulation of lymphocytes, and the production of macrophage migration inhibition factor by most of these substances. These results suggest that bacterial factors may play a prominent role as aetiological agents in at least some cases of intrinsic asthma. In intrinsic asthma there was a high incidence of tissue autoantibodies, whereas the incidence was negligible in patients with atopic asthma. The level of serum immunoglobulins was not statistically different between the two groups of patients except for IgE. The patients with intrinsic asthma showed a favorable response to sodium cromoglycate.
