Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum

Pinton, Paolo; Rizzuto, Rosario

doi:10.1038/sj.cdd.4401960

Cited by 226 publications

(188 citation statements)

References 78 publications

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“…Transgenic islets expressing BCL-X L had a general secretory impairment, including a lack of response to KCl, tolbutamide and KIC 36 . This is consistent with the function of BCL-X L at the endoplasmic reticulum and probably reflects perturbations in Ca 2+ homeostasis associated with BCL-X L overexpression 4 . In contrast to BCL-X Loverexpressing islets, the glucose-selective defect of Bad −/− islets is consistent with a functional and biochemical interaction between BAD and glucokinase, which can be pharmacologically manipulated by a BAD BH3 helix that has been chemically reinforced by the hydrocarbon-stapling synthetic strategy.…”

Section: Discussionsupporting

confidence: 67%

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Dual role of proapoptotic BAD in insulin secretion and beta cell survival

Danial

Walensky

Zhang

et al. 2008

Nat Med

296

377

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Section: Discussionsupporting

confidence: 67%

“…Recent studies have assigned new roles to certain BCL-2 family members in other physiologic pathways, such as metabolism 2,3 , Ca 2+ homeostasis 4 and mitochondrial morphology 5 . Whether such roles represent separate functions for these proteins, which are primarily defined as regulators of cell death, is a topic under active investigation.…”

mentioning

confidence: 99%

Dual role of proapoptotic BAD in insulin secretion and beta cell survival

Danial

Walensky

Zhang

et al. 2008

Nat Med

296

377

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“…It is difficult to predict the effect of mutations on BCL2 function due to its pleiotropism, with known roles in autophagy, ER Ca 2 þ storage, 53 cell-cycle entry and apoptosis, in which it can act as protector or killer. BCL2 function also varies depending on which genes are co-expressed, and whether those genes are also mutated.…”

Section: Discussionmentioning

confidence: 99%

BCL2 mutations in diffuse large B-cell lymphoma

et al. 2011

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BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-kB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.Leukemia ( BCL2, discovered because of its involvement in t(14;18) in follicular lymphoma (FL), 3 has a central role in the inhibition of apoptosis. 4 BCL2 is normally transiently expressed during B-cell maturation. The t(14;18) translocation causes constitutive overexpression of BCL2 by juxtaposing it to immunoglobulin heavy chain gene enhancer elements. This translocation is found in B20% of DLBCL, 5 most often in the GCB subtype of DLBCL. 6 Other mechanisms of BCL2 deregulation, more often observed in ABC DLBCLs, include amplification of the BCL2 gene or its transcriptional upregulation through constitutive activation of the nuclear factor-kB pathway. 7 Saito et al. 8 reported that the BCL2 promoter can also be aberrantly hypermutated in DLBCL, which may prevent its inhibition by MIZ1 and BCL6. 8 They found a high number of mutations in BCL2 and suggested that the mutations described were the result of somatic hypermutation (SHM). Mutations in BCL2 have been shown to cause false-negative protein expression results in immunohistochemistry assays in FL; 9,10 however, no large study has so far investigated whether this occurs in DLBCL.

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“…However, there is previous literature demonstrating that CHOP could downregulate the expression of Bcl-2 (15) and ER stress-induced cell death involves a caspase and Bax-dependent pathway (24). In addition, in case of ER stress occurrence, there is sustained release of Ca 2+ from the ER, the cation may be taken up by mitochondria localised in the Ca 2+ microdomain, with subsequent mitochondrial membrane permeabilisation and cell death (25).…”

Section: Discussionmentioning

confidence: 99%

Tubeimoside-1 induces G2/M phase arrest and apoptosis in SKOV-3 cells through increase of intracellular Ca2+ and caspase-dependent signaling pathways

Yang

2011

Int J Oncol

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Abstract. Tubeimoside-1 (TBMS1) extracted from Bolbostemma paniculatum (Maxim), is a traditional Chinese herb with anticancer potential. It induces apoptosis in a number of human carcinoma cell lines, but the mechanism has remained unclear.In the present study, we investigated the pro-apoptotic activity of TBMS1 against SKOV-3 cell lines and the underlying mechanisms. Treatment with TBMS1 resulted in dose-and time-dependent inhibition of proliferation, led to arrest in phase G 2 /M of the cell cycle and increased the levels of intracellular Ca 2+ . Furthermore, TBMS1 up-regulated the levels of the glucose-regulated protein 78/immunoglobuin heavy chain binding protein (GRP78/Bip), C/EBP homologous protein (CHOP), Bax, and cleaved caspase-3 and down-regulated the levels of Bcl-2. It was shown to be linked to activation of the extracellular signal-regulated kinase (ERK) 1 and 2 signal transduction pathway. A decrease in Bcl-2/Bax ratio with increased expression of caspase-3, and intracellular Ca 2+ provide compelling evidence that TBMS1-induced apoptosis is mediated by the mitochondrial pathway. The results of the present study suggest that TBMS1 has immense potential in cancer prevention and therapy based on its antiproliferative and apoptosis inducing effects.

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Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum

Cited by 226 publications

References 78 publications

Dual role of proapoptotic BAD in insulin secretion and beta cell survival

Dual role of proapoptotic BAD in insulin secretion and beta cell survival

BCL2 mutations in diffuse large B-cell lymphoma

Tubeimoside-1 induces G2/M phase arrest and apoptosis in SKOV-3 cells through increase of intracellular Ca2+ and caspase-dependent signaling pathways

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