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J. Biol. Chem., Vol. 277, Issue 46, 43771-43777, November 15, 2002
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From the Department of Molecular Physiology, National
Cardiovascular Center Research Institute, Fujishiro-dai 5-7-1, Suita,
Osaka 565-8565, Japan
The calcineurin B homologous protein
(designated CHP1) has been shown to be a common essential cofactor for
the plasma membrane Na+/H+ exchangers
(NHEs) (Pang, T., Su, X., Wakabayashi, S., and Shigekawa, M. (2001)
J. Biol. Chem. 276, 17367-17372). In this
study, we characterized the function of another isoform of CHP
(designated CHP2) that has a 61% amino acid identity with CHP1. CHP2,
like CHP1, conferred the ability to NHEs 1-3 to express a high
exchange activity by binding to the juxtamembrane region of the
cytoplasmic domain of the exchanger, but it interacts more strongly
(~5-fold) with NHE1 than does CHP1. Although CHP1 is expressed
ubiquitously at relatively high levels, CHP2 expression was extremely
low in most human tissues but was higher in tumor cells. We produced stable cell clones overexpressing either CHP1 or CHP2 in which one of
them is predominantly bound to NHE1. Serum (10%) induced a significant
cytoplasmic alkalinization (0.1-0.2 pH unit) in cells co-expressing
CHP1 and NHE1 but not in cells co-expressing CHP2 and NHE1. In the
latter, pHi was high (7.4-7.5) even in the absence of
serum, suggesting that NHE1 was already activated. Surprisingly, most
(>80%) of CHP2/NHE1 cells unlike CHP1/NHE1 cells were viable even
after long serum starvation (>7 days). Thus, the expression of CHP2
appears to protect cells from serum deprivation-induced death by
increasing pHi. These properties of CHP2/NHE1 cells are similar
to those of malignantly transformed cells. We propose that
serum-independent activation of NHE1 by bound CHP2 is one of the key
mechanisms for the maintenance of high pHi and the resistance
to serum deprivation-induced cell death in malignantly transformed cells.
The amino acid sequence of this protein can be accessed
through NCBI Protein Database under NCBI accession number
NM_022097. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF146019.
Expression of Calcineurin B Homologous Protein 2 Protects Serum
Deprivation-induced Cell Death by Serum-independent Activation of
Na+/H+ Exchanger*
,
*
This work was supported by Grant-in-aid for Priority Areas
13142210 and Grant-in-aid for Scientific Research 14580664 from the
Ministry of Education, Science, and Culture of Japan and by the
promotion of Fundamental Studies in Health Science of the Organization
for Pharmaceutical Safety and Research of Japan.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.
Supported by a Japan Society for the Promotion of Science
Postdoctoral Fellowship.
§
To whom correspondence should be addressed. Tel.:
81-6-6833-5012; Fax: 81-6-6872-7485; E-mail: wak@ri.ncvc.go.jp.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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