The polymorphic 43Thr bcl-2 protein confers relative resistance to autoimmunity: an analytical evaluation

Komaki, Satoru; Kohno, Michifumi; Matsuura, Nobuo; Shimadzu, Mitsunobu; Adachi, Naoto; Hoshide, Ryuuji; Nishiyama, Soroku; Matsuda, Ichiro

doi:10.1007/s004390050847

Cited by 32 publications

(26 citation statements)

References 26 publications

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“…Also, the anti-apoptotic molecule, bcl-2, maps to the IDDM6 region. One Japanese study 137 has reported an association of T1D with an Ala43Thr polymorphism of BCL2; however, this association has not been confirmed in a recent study of different Caucasoid populations. 138 Several loci on chromosome 2q have been linked to T1D.…”

Section: Iddm2-the Insulin Gene (Ins) Regionmentioning

confidence: 85%

Genetics of type 1 diabetes mellitus

2002

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Section: Iddm2-the Insulin Gene (Ins) Regionmentioning

confidence: 85%

Genetics of type 1 diabetes mellitus

2002

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“…Although 28/51 unique non-synonymous mutations were marked 'benign' by PolyPhen, this does not preclude a functional role. For example, non-synonymous mutations at residue A43 were scored as 'benign' by PolyPhen; but previous work 47 has shown that changes at this position provide resistance to autoimmunity via reduction of T cells.…”

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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“…Since synergistic effects of Bcl-2 genotypes and cytokine abnormalities have been reported to predispose to disease expression, 41,42 further dissection of the mechanisms and regulation of propriocidal and cytokine-induced cell death may lead to a better understanding of the pathogenesis of SLE. …”

Section: Discussionmentioning

confidence: 99%

Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus

et al. 2000

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Both faulty regulation of apoptosis and the inappropriate expression of several interleukins have been considered important defects of lymphocytes in the human autoimmune disease systemic lupus erythematosus (SLE). We therefore tested the in vitro effect of recombinant interleukin (IL-)-2, 4, 7, and 15 on peripheral blood mononuclear cells from patients with SLE and from healthy volunteers. Intracellular Bcl-2 and Bax expression was measured by fluorocytometry and the rate of apoptosis was determined by the TUNEL technique and propidium iodide staining. IL-2, IL-4, IL-7 and IL-15 led to a significant increase in Bcl-2 and a reduction in cell death rates, which was even more pronounced in SLE. Bax levels remained unchanged. Interestingly, the high ex vivo Bcl-2 content of lymphocytes from some SLE patients was maintained after growth factor withdrawal. Anti-apoptotic cytokine signaling may significantly influence the deregulation of cell death in SLE lymphocytes. Cell Death and Differentiation (2000) 7, 966 ± 972.

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The polymorphic 43Thr bcl-2 protein confers relative resistance to autoimmunity: an analytical evaluation

Cited by 32 publications

References 26 publications

Genetics of type 1 diabetes mellitus

Genetics of type 1 diabetes mellitus

BCL2 mutations in diffuse large B-cell lymphoma

Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus

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