Assistant Professor of Medicine
Molecular Mechanisms of
Critical Care Division
Royal Victoria Hospital
687 Pine Avenue West
Montreal, QC H4B 2S5
Tel: (514) 843-1664
Fax: (514) 843-1686
arnold [dot] kristof [at] muhc [dot] mcgill [dot] ca (Email)
1. Regulation of nitric oxide synthesis
Initiation of human inducible nitric oxide synthase gene transcription is the primary regulatory mechanism by which large amounts of nitric oxide are produced in the presence of inflammatory mediators, such as cytokines and lipopolysaccharide.
I am currently studying the role of cytokine-inducible signaling pathways, including tyrosine and lipid kinases, in activation of the human inducible nitric oxide promoter. In addition, I am assessing the role of known and novel transcription factors, as well as putative promoter binding sequences, in human iNOS transcriptional activation.
2. Regulation of Signal Transducer and Activator of Transcription-1 (STAT1)
STAT1 is required for the activation of iNOS transcription, as well as the activation of other pro-inflammatory and pro-apoptotic genes.
We recently discovered that a protein kinase, mammalian target of rapamycin (mTOR), forms a complex with STAT1, and regulates STAT1 transcriptional activity, in response to lipopolysaccharide and interferon-g. I am currently studying the molecular determinants of the mTOR/STAT1 interaction, in addition to defining other proteins in this regulatory complex.
3. Abnormal cellular proliferation in lung disease
Lung epithelial cell apoptosis and proliferation play an important role in the airway injury and remodeling observed in asthma, cystic fibrosis, chronic obstructive pulmonary disease, acute lung injury, and pneumonitides.
I am currently interested in assessing epithelial cell signaling pathways that control proliferation and apoptosis (i.e., mTOR, STAT1, iNOS, PI3K), and their role in airway injury and repair. Pharmacological agents that target these signaling pathways have been characterized, and represent powerful tools to study their contribution to the pathophysiology of lung disease.
Selected Recent Publications
Kristof AS, Marks-Konczalik J, Billings E, Moss J. "Stimulation of signal transducer and activator of transcription-1 (STAT1)-dependent gene transcription by lipopolysaccharide and interferon-gamma is regulated by mammalian target of rapamycin." J Biol Chem. 2003 Sep 5; 278(36):33637-44. Epub 2003 Jun 14.
Kristof AS, Marks-Konczalik J, Moss J. "Mitogen-activated protein kinases mediate activator protein-1-dependent human inducible nitric-oxide synthase promoter activation." J Biol Chem. 2001 Mar 16; 276(11):8445-52. Epub 2000 Dec 08.
Kristof AS, Goldberg P, Laubach V, Hussain SN. "Role of inducible nitric oxide synthase in endotoxin-induced acute lung injury." Am J Respir Crit Care Med. 1998 Dec; 158(6):1883-9.