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J. Biol. Chem., Vol. 277, Issue 22, 19255-19264, May 31, 2002
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From the Calreticulin is a Ca2+-binding
molecular chaperone of the lumen of the endoplasmic reticulum.
Calreticulin has been shown to be essential for cardiac and neural
development in mice, but the mechanism by which it functions in cell
differentiation is not fully understood. To examine the role of
calreticulin in cardiac differentiation, the calreticulin gene was
introduced into rat cardiomyoblast H9c2 cells, and the effect of
calreticulin overexpression on cardiac differentiation was examined.
Upon culture in a differentiation medium containing fetal calf serum
(1%) and retinoic acid (10 nM), cells transfected with the
calreticulin gene were highly susceptible to apoptosis compared with
controls. In the gene-transfected cells, protein kinase B/Akt signaling
was significantly suppressed during differentiation. Furthermore,
protein phosphatase 2A, a Ser/Thr protein phosphatase, was
significantly up-regulated, implying suppression of Akt signaling due
to dephosphorylation of Akt by the up-regulated protein phosphatase 2A
via regulation of Ca2+ homeostasis. Thus, overexpression of
calreticulin promotes differentiation-dependent apoptosis in H9c2 cells by suppressing the Akt signaling pathway. These findings indicate a novel mechanism by which cytoplasmic Akt
signaling is modulated to cause apoptosis by a resident protein of the
endoplasmic reticulum, calreticulin.
Overexpression of Calreticulin Modulates Protein Kinase B/Akt
Signaling to Promote Apoptosis during Cardiac Differentiation of
Cardiomyoblast H9c2 Cells*
§¶,
¶
,
,
,
Department of Biochemistry and
Molecular Biology in Disease, Atomic Bomb Disease Institute, and the
§ Third Department of Internal Medicine, Nagasaki University
School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
*
This work was supported in part by grants-in-aid from the
Ministry of Education, Science, Sports, and Culture of Japan and by the
Japan Foundation of Cardiovascular Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
81-95-849-7099; Fax: 81-95-849-7100; E-mail:
y-ihara@net.nagasaki-u.ac.jp.
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