Sustained ER Ca2+ depletion suppresses protein synthesis and induces activation-enhanced cell death in mast cells.

نویسندگان

  • Jonathan Soboloff
  • Stuart A Berger
چکیده

Depletion of Ca(2+) from the endoplasmic reticulum (ER) induces large increases in cytoplasmic Ca(2+), mitochondrial Ca(2+) loading, protein synthesis inhibition, and cell death. To clarify the connections among these events, we have evaluated the effect of Ca(2+) mobilizing agents thapsigargin (Tg), econazole (Ec), and the growth factor Steel Factor (SLF) on bone marrow-derived mast cells (BMMCs). BMMC Ca(2+) stores were found to consist of a Tg-sensitive ER compartment, the Tg-insensitive SIC store, and mitochondrial stores. Low levels of Ec interfered with Tg-stimulated mitochondrial loading while promoting progressive leakage of Ca(2+) from the ER. Low levels of Ec completely reversed Tg toxicity while higher levels blocked store-operated influx and induced cell death in a SLF-enhanced manner. Both Ec and Tg inhibited protein synthesis, however, only SLF plus Tg or very high levels of Ec were able to significantly stimulate EIF-2alpha phosphorylation. Cycloheximide only partially protected BMMCs from Tg toxicity yet strongly synergized with Ec to induce cell death. These results therefore indicate that although both Tg and Ec deplete ER Ca(2+) levels, Ec-induced cell death results from sustained protein synthesis inhibition while Tg toxicity results primarily from mitochondrial Ca(2+) overload and secondarily from ER stress associated with Ca(2+) depletion.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

O-31: Mifepristone Acts as Progesterone Antagonistof Non-Genomic Responses but InhibitsPhytohemagglutinin Induced Proliferationin Human T Cells

Background: Progesterone is an endogenous immunomodulator that suppresses T cell activation during pregnancy. The stimulation of membrane progesterone receptors (mPRs) would seem to be the cause of rapid non-genomic responses in human peripheral T cells, such as an elevation of intracellular calcium ([Ca2+] i) and decreased intracellular pH (pHi). Mifepristoneimmune cells compared with progeste...

متن کامل

Depletion of intracellular Ca2+ by caffeine and ryanodine induces apoptosis of chinese hamster ovary cells transfected with ryanodine receptor.

Recent studies have suggested a central role for Ca(2+) in the signaling pathway of apoptosis and certain anti-apoptotic effects of Bcl-2 family of proteins have been attributed to changes in intracellular Ca(2+) homeostasis. Here we report that depletion of Ca(2+) from endoplasmic reticulum (ER) leads to apoptosis in Chinese hamster ovary cells. Stable expression of ryanodine receptor (RyR) in...

متن کامل

Activation of human lung mast cells by monomeric immunoglobulin E.

The mechanism of chronic mast cell activation in asthma is unclear. Monomeric immunoglobulin (Ig)E in the absence of allergen induces mediator release from rodent mast cells, indicating a possible role for IgE in the continued activation of mast cells within the asthmatic bronchial mucosa. In this study it was investigated whether monomeric IgE induces Ca2+ influx and mediator release from huma...

متن کامل

A function for tyrosine phosphorylation of type 1 inositol 1,4,5-trisphosphate receptor in lymphocyte activation

Sustained elevation of intracellular calcium by Ca2+ release-activated Ca2+ channels is required for lymphocyte activation. Sustained Ca2+ entry requires endoplasmic reticulum (ER) Ca2+ depletion and prolonged activation of inositol 1,4,5-trisphosphate receptor (IP(3)R)/Ca2+ release channels. However, a major isoform in lymphocyte ER, IP3R1, is inhibited by elevated levels of cytosolic Ca2+, an...

متن کامل

Endoplasmic reticulum stress in the proapoptotic action of edelfosine in solid tumor cells.

The endoplasmic reticulum (ER) has been posited as a potential anticancer target. The synthetic antitumor alkyl-lysophospholipid analogue edelfosine accumulates in the ER of solid tumor cells. This ER accumulation of the drug leads to the inhibition of phosphatidylcholine and protein synthesis, G(2)-M arrest, depletion of ER-stored Ca(2+), Bax up-regulation and activation, transcriptional facto...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • The Journal of biological chemistry

دوره 277 16  شماره 

صفحات  -

تاریخ انتشار 2002