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Bid Regulates Murine Hepatocyte Proliferation by Controlling ER Calcium Homeostasis
Author(s) -
Li Min,
Ni Hongmin,
Baty Catherine J.,
Ding Wenxing,
Chen Xiaoyun,
Yin Xiaoming
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.749.5
Subject(s) - hepatocyte , microbiology and biotechnology , chemistry , endoplasmic reticulum , calcium , ionomycin , thapsigargin , liver regeneration , calcium metabolism , cell growth , homeostasis , calcium in biology , medicine , endocrinology , intracellular , biology , regeneration (biology) , biochemistry , organic chemistry , in vitro
Bid, a BH3‐only Bcl‐2 family molecule, is generally known for its importance in activating the mitochondrial apoptosis pathway following death receptor engagement, particularly in hepatocytes. However, Bid also promotes hepatocyte proliferation during liver regeneration and carcinogenesis. This study aimed to determine the mechanism by which Bid regulated hepatocyte proliferation. Wild type and bid ‐deficient primary hepatocytes were stimulated with serum and proliferation was measured by BrdU incorporation and immunoblot analysis of key cell cycle molecules. The hypothesis that Bid regulated endoplasmic reticulum (ER) calcium ([Ca 2+ ] ER ) homeostasis to affect proliferation was examined by measuring intracellular calcium level, by modulating the calcium level with pharmacological agents and by subcellular localization assay. We found that serum stimulated hepatocyte proliferation was dependent on calcium and depletion of calcium using thapsigargin or EGTA inhibited the proliferation. A portion of Bid was present in the ER and Bid negatively regulated [Ca 2+ ] ER level, which was responsible for the delayed and reduced proliferation in bid ‐deficient hepatocytes. Addition of ionomycin or reconstitution of Bid, particularly an ER‐targeted Bid, corrected the deficiency. In conclusion, we have revealed a novel regulatory mechanism of hepatocyte proliferation, exerted by Bid, a Bcl‐2 family protein otherwise known for its pro‐apoptosis activity under stress condition. This mechanism is mediate by the regulation on ER calcium homeostasis. We consider that this mechanism would be important for liver regeneration and carcinogenesis.