Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	CRM1 Protein-mediated Regulation of Nuclear Clusterin (nCLU), an Ionizing Radiation-stimulated, Bax-dependent Pro-death Factor
Δημιουργός/Συγγραφέας:	Leskov, Konstantin S. Araki, Shinako Lavik, John-Paul Gomez, Jose A. Gama, Vivian [EL] Γκόνος, Ευστάθιος[EN] Gonos, Efstathios S. [EL] Τρουγκάκος, Ιωάννης Π.[EN] Trougakos, Ioannis P. Matsuyama, Shigemi Boothman, David A.
Εκδότης:	American Society for Biochemistry and Molecular Biology, Inc.
Τόπος έκδοσης:	BETHESDA
Ημερομηνία:	2011-11-18
Γλώσσα:	Αγγλικά
ISSN:	0021-9258
DOI:	10.1074/jbc.M111.252957
Περίληψη:	Expression of the clusterin (CLU) gene results in the synthesis of a conventional secretory isoform set (pre- and mature secretory clusterin proteins, psCLU/sCLU), as well as another set of intracellular isoforms, appearing in the cytoplasm (pre-nuclear CLU, pnCLU) and in the nucleus as an similar to 55-kDa mature nuclear clusterin (nCLU) form. These two isoform sets have opposing cell functions: pro-survival and pro-death, respectively. Although much is known about the regulation and function of sCLU as a pro-survival factor, the regulation and function of endogenous nCLU in cell death are relatively unexplored. Here, we show that depletion of endogenous nCLU protein using siRNA specific to its truncated mRNA increased clonogenic survival of ionizing radiation (IR)-exposed cells. nCLU-mediated apoptosis was Bax-dependent, and lethality correlated with accumulation of mature nCLU protein. nCLU accumulation was regulated by CRM1 because binding between CRM1 and nCLU proteins was significantly diminished by leptomycin B (LMB), and nuclear levels of nCLU protein were significantly enhanced by LMB and IR co-treatment. Moreover, LMB treatment significantly enhanced IR-induced nCLU-mediated cell death responses. Importantly, bax(-/-) and bax(-/-)/bak(-/-) double knock-out cells were resistant to nCLU-mediated cell death, whereas bak(-/-) or wild-type bax(+/+)/bak(+/+) cells were hypersensitive. The regulation of nCLU by CRM1 nuclear export/import may explain recent clinical results showing that highly malignant tumors have lost the ability to accumulate nCLU levels, thereby avoiding growth inhibition and cell death.
Τίτλος πηγής δημοσίευσης:	Journal of Biological Chemistry
Τόμος/Κεφάλαιο:	286
Τεύχος:	46
Σελίδες:	40083-40090
Θεματική Κατηγορία:	[EL] Βιοχημεία[EN] Biochemistry
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Ηλεκτρονική διεύθυνση περιοδικού (link) :	http://www.jbc.org/
ΙΒΦΧΒ: αρχειακή συλλογή:	Ινστιτούτο Βιολογικών Ερευνών και Βιοτεχνολογίας (ΙΒΕΒ) (έως 2012)
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο