title: HMGA2 inhibits apoptosis through interaction with ATR-CHK1 signaling complex in human cancer cells.
abstract: The non-histone chromatin binding protein high mobility group AT-hook 2 (HMGA2) is expressed in stem cells and many cancer cells, including tumor initiating cells, but not translated in normal human somatic cells. The presence of HMGA2 is correlated with advanced neoplastic disease and poor prognosis for patients. We had previously demonstrated a role of HMGA2 in DNA repair pathways. In the present study, we employed different human tumor cell models with endogenous and exogenous expression of HMGA2 and show that upon DNA damage, the presence of HMGA2 caused an increased and sustained phosphorylation of the ataxia telangiectasia and Rad3-related kinase (ATR) and its downstream target checkpoint kinase 1 (CHK1). The presence of activated pCHK1(Ser296) coincided with prolonged G2/M block and increased tumor cell survival, which was enhanced further in the presence of HMGA2. Our study, thus, identifies a novel relationship between the ATR-CHK1 DNA damage response pathway and HMGA2, which may support the DNA repair function of HMGA2 in cancer cells. Furthermore, our data provide a rationale for the use of inhibitors to ATR or CHK1 and HMGA2 in the treatment of HMGA2-positive human cancer cells.
authors.affiliation: Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Suchitra
authors.initials: S
authors.lastname: Natarajan
authors.forename: Sabine
authors.initials: S
authors.lastname: Hombach-Klonisch
authors.forename: Peter
authors.initials: P
authors.lastname: Dröge
authors.forename: Thomas
authors.initials: T
authors.lastname: Klonisch
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects; D015870:Gene Expression; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D025743:HMGA2 Protein; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D006918:Hydroxyurea