Identification of LKB1 kinase substrates involved in suppression of lung adenocarcinoma cell growth

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http://urn.fi/URN:NBN:fi:hulib-202109013609
Title: Identification of LKB1 kinase substrates involved in suppression of lung adenocarcinoma cell growth
Author: Siskovs, Klims
Contributor: University of Helsinki, Faculty of Medicine
Publisher: Helsingin yliopisto
Date: 2021
Language: eng
URI: http://urn.fi/URN:NBN:fi:hulib-202109013609
http://hdl.handle.net/10138/333903
Thesis level: master's thesis
Degree program: Translationaalisen lääketieteen maisteriohjelma (Translational Medicine)
Master's Programme in Translational Medicine
Magisterprogrammet i translationell medicin
Specialisation: Cross-disciplinary translational medicine
Cross-disciplinary translational medicine
Cross-disciplinary translational medicine
Abstract: STK11/LKB1 is a tumor suppressor gene and mutated in 18% of lung adenocarcinomas. Tumor suppressor liver kinase B1 (LKB1) is known to activate adenosine monophosphate-activated protein kinase (AMPK) and 12 AMPK-related kinases (ARKs) by phosphorylating a conserved threonine residue in their T-loop region. A number of studies focused on investigating the influence of LKB1-AMPK signaling on cancer cell proliferation. However, there is no systematic study for identifying the critical LKB1 kinase substrates in suppressing lung cancer cell growth. In this project, the LKB1-deficient lung adenocarcinoma cell line A549 cells were sequentially overexpressed with constitutively active mutants of AMPKα1, AMPKα2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3. The overexpression status was confirmed at both genetic and protein levels by qPCR and Western blotting, correspondingly. In vitro growth assays demonstrated up to 33% reduced growth rate of A549 cells overexpressing AMPKα1, AMPKα2 and NUAK1. Furthermore, siRNA knockdown of the selected substrates in LKB1-overexpressing A549 cells significantly rescued the cell growth defect. These findings suggest, that AMPKα1, AMPKα2 and NUAK1 kinases are critical for LKB1-mediated cell growth defect in lung adenocarcinoma.
Subject: LKB1
AMPK
NUAK1
lung adenocarcinoma
ARKs
growth defect
tumor suppressor


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