IRAS is an anti-apoptotic protein.
Active cell death, also known as apoptosis, has been implicated in the pathophysiology of diseases such as cancer, heart failure and neurodegenerative disorders. We report the anti-apoptotic function of IRAS, which was previously shown to bind imidazoline ligands. The amino acid sequence of human IRAS (hIRAS) is unrelated to known proteins, except for rat IRAS and a mouse homologue named nischarin, which binds the alpha5 integrin subunit of the fibronectin receptor. When stably transfected into PC12 cells, hIRAS localizes to the cytosol as a 167 kDa immunoreactive protein. Clonal PC12 cell lines expressing hIRAS displayed normal serum growth responses. However, hIRAS expression led to prolonged cell survival against known apoptotic stimuli: serum starvation or thapsigargin or staurosporine treatments. The apoptotic population of hIRAS-expressing cells was significantly reduced, and this protection was achieved by a decrease in caspase-3 activity, phosphatidylserine translocation, and nuclear fragmentation. Similar protective effect was obtained in COS7 cells transiently transfected with hIRAS. A partial activation of the PI3 kinase pathway is possibly implicated in the anti-apoptotic effect of IRAS. Thus, IRAS appears to represent a previously unknown anti-apoptotic protein involved in the regulation of cell survival.
Dontenwill
Monique
M
Pharmacologie et Physicochimie des Interactions Cellulaires et Moléculaires, UMR CNRS 7034, Faculté de Pharmacie, Université Louis Pasteur de Strasbourg, Illkirch, France. mdontenwill@aspirine.u-strasbg.fr
Piletz
John E
JE
Chen
Michael
M
Baldwin
James
J
Pascal
Geraldine
G
Ronde
Philippe
P
Dupuy
Laurence
L
Greney
Hugues
H
Takeda
Ken
K
Bousquetd
Pascal
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002867:Chromones / Q000378:metabolism; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D054755:Imidazoline Receptors; D039081:Integrin alpha5beta1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009025:Morpholines / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019311:Staurosporine / Q000378:metabolism
D002352:Carrier Proteins; D002867:Chromones; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D054755:Imidazoline Receptors; D039081:Integrin alpha5beta1; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; C458505:NISCH protein, human; D011955:Receptors, Drug; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011972:Receptor, Insulin; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine