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Hint1, Hint2, apoptosis and proliferation

English title Hint1, Hint2, apoptosis and proliferation
Applicant Dufour Jean-François
Number 125399
Funding scheme Project funding (Div. I-III)
Research institution Institut für Klinische Pharmakologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Physiology : other topics
Start/End 01.04.2009 - 31.03.2012
Approved amount 375'000.00
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Keywords (7)

mitochondria; apoptosis; tumor suppressor; liver regeneration; steatohepatitis; cancer; HINT proteins

Lay Summary (English)

Lead
Lay summary
Hint proteins are small soluble proteins which have been highly conserved though evolution. They are characterized by a special amino-acid motif which can bind nucleotides. Hint1 is expressed in all cells in the cytoplasm and the nucleus. We and others found that Hint1 protect against the development of tumors. Hint2 is different from Hint1. We found that is localized in a cellular organelle important to produce energy, the mitochondria and that Hint2 affects the function of this small power plant. Hint2 is important to regulate the resistance of the cells to stresses which lead the cell to commit suicide, a process called apoptosis. We research is focused on elucidating the mechanism of action of these proteins as well as their importance in pathophysiology.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Hit proteins, mitochondria and cancer
Martin J, St-Pierre MV, Dufour JF (2011), Hit proteins, mitochondria and cancer, in BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 1807(6), 626-632.
Ablation of the tumor suppressor histidine triad nucleotide binding protein 1 is protective against hepatic ischemia/reperfusion injury.
Martin Juliette, Romanque Pamela, Maurhofer Olivier, Schmitter Karin, Hora Caroline, Ferrand Gisèle, Dufour Jean-François (2011), Ablation of the tumor suppressor histidine triad nucleotide binding protein 1 is protective against hepatic ischemia/reperfusion injury., in Hepatology (Baltimore, Md.), 53(1), 243-52.
HINT1 IS A PROTEIN POTENTIALLY IMPLICATED IN LIVER REGENERATION
Hora C, Maurhofer O, Ledermann M, Ferrand G, Li H, Weinstein IB, Dufour JF, Martin J (2009), HINT1 IS A PROTEIN POTENTIALLY IMPLICATED IN LIVER REGENERATION, in JOURNAL OF HEPATOLOGY, 50, 308-308.
HINT1 KNOCK-OUT MICE ARE RESISTANT TO HEPATIC ISCHEMIA/REPERFUSION INJURY
Maurhofer O, Romanque P, Schmitter K, Ledermann M, Ferrand G, Li H, Weinstein IB, Dufour JF, Martin J (2009), HINT1 KNOCK-OUT MICE ARE RESISTANT TO HEPATIC ISCHEMIA/REPERFUSION INJURY, in JOURNAL OF HEPATOLOGY, 50, 14-14.
HEPATIC ISCHEMIA/REPERFUSION INJURY IS PREVENTED BY THE DELETION OF HINT1
Maurhofer O, Romanque P, Schmitter K, Ledermann M, Ferrand G, Li HY, Dufour JF, Martin J (2009), HEPATIC ISCHEMIA/REPERFUSION INJURY IS PREVENTED BY THE DELETION OF HINT1, in HEPATOLOGY, 50(4), 352-352.
HINT1 DELETION IMPAIRS LIVER REGENERATION
Hora C, Maurhofer O, Ledermann M, Ferrand G, Dufour JF, Martin J (2009), HINT1 DELETION IMPAIRS LIVER REGENERATION, in HEPATOLOGY, 50(4), 626-626.
Ablation of histidine triad nucleotide-binding protein-1 (HINT1) increases sensitivity to hepatocellular carcinoma
Martin J, Piguet AC, Ledermann M, Saar B, Wilkens L, Ferrand G, Li H, Weinstein IB, Dufour JF (2008), Ablation of histidine triad nucleotide-binding protein-1 (HINT1) increases sensitivity to hepatocellular carcinoma, in JOURNAL OF HEPATOLOGY, 48, 36-36.

Associated projects

Number Title Start Funding scheme
140930 Hint1 and Hint2: a closer look at mechanisms 01.04.2012 Project funding (Div. I-III)
160001 Hint2 and nutritional stress 01.04.2015 Project funding (Div. I-III)
139231 Advancement of functional genomics research at the University of Bern by extension of LC-MS platform 01.07.2012 R'EQUIP
112173 Hint2, a mitochondrial tumor suppressor 01.04.2006 Project funding (Div. I-III)

Abstract

HIstidine triad NucleoTide-binding (HINT) proteins, are nucleoside phosphoraminidases present in all forms of life, but still of uncertain biological function. Our research concentrates on identifying the roles of the human HINT1 and HINT2, two structurally similar proteins with different tissue and subcellular localizations. Pursuant to our findings that HINT1 increases susceptibility to hepatocarcinogenesis, impairs liver regeneration and protects against IR injury, we will now unravel its mechanisms of action. Pursuant to our discovery that HINT2 impair mitochondrial functions, we will examine its relevance in the human mitochondrial associated processes of ageing, Parkinsonism and insulin resistance. With the successful engineering of Hint2 deleted mice and our preliminary work in Hint1 deleted mice, we are now able to embark on comparative experiments that will distinguish the common and distinct signalling pathways that engage the two murine Hint proteins and thereby identify human diseases that implicate the function of either or both human HINT1 and HINT2.
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