Dissecting the signaling pathways that mediate cancer in PTEN and LKB1 double-knockout mice.
Double knockout of PTEN and LKB1-genes encoding phosphatase and tensin homolog and liver kinase B1, respectively-leads to the spontaneous development of cancer in mice. PTEN converts phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-bisphosphate (PIP2), whereas LKB1 activates the 5' adenosine monophosphate-activated protein kinase (AMPK). The kinase AKT and the kinase complex mTORC1 may play key roles in carcinogenesis and are components of signaling pathways that also contain PTEN and LKB1. We propose that via activation of AKT and mTORC1, the double knockout of PTEN and LKB1 contributes to distinct cell-specific aspects of tumor development and progression. Whereas mTORC1 promotes cancer initiation and progression through cell growth, survival, and proliferation, independent induction of the immune inhibitory molecule PD-L1 by activated AKT enables the tumors to evade immunosurveillance.
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia. School of Biomedical Sciences, University of Queensland, St Lucia, QLD4072, Australia. jiezhong.chen@newcastle.edu.au christopher.proud@sahmri.com.
Jiezhong
J
Chen
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia.
Xu Dong
XD
Zhang
South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia. jiezhong.chen@newcastle.edu.au christopher.proud@sahmri.com.
Christopher
C
Proud
D055372:AMP-Activated Protein Kinases; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D019139:Tumor Escape
D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse