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Entity | Lymphoma and leukemia |
Note | Lymphomas and leukemias have high levels of Bcl-2 prosurvival proteins that prevent Bak (and Bax) from inducing apoptosis. New anti-cancer therapies that target prosurvival proteins can activate Bak (or Bax) to re-instate apoptotic cell death. In one example, a new drug, GX15-070, was found to induce apoptosis in mantle cell lymphoma cell lines by binding to Mcl-1 and assist in Bak activation (Pérez-Galán et al., 2007). This drug is in clinical trials for refractory chronic lymphocytic leukemia (Storey, 2008), and is presumably acting by indirectly activating Bak (or Bax). |
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Entity | Gastric and colorectal cancer |
Note | The first report of Bak mutations being associated with gastrointestinal cancers was of missense BAK1 mutations in 3 of 24 gastric cancers and 2 of 20 colorectal cancers, with mutations observed only in advanced-stage cancers (Kondo et al., 2000). In another study, BAK1 mutations were also rare (3/107) in patients with gastric adenocarcinomas, and were each associated with late stage disease (Kim et al., 2003). However, no somatic mutations were found in 192 patients with colorectal and gastric cancers, and the rare single-nucleotide substitutions (4/129) were also found in the corresponding normal tissue samples (Sakamoto et al., 2004). |
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Entity | Uterine cervical carcinoma |
Note | Possible role for Bak mutation in uterine cervical carcinoma was reported (Wani et al., 2003). In a study of 42 patients, 6 missense (M60V, D30N, D57N, V74M, I80T and V191A) and one silent mutations in the coding region of BAK1 were found, with no mutations detected in 32 non-neoplastic cervix tissue samples. Mutations were associated with late-stage disease and with resistance to chemotherapy, but were not statistically significant due to sample size. |
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Entity | Melanoma |
Note | In patients with superficial-spreading melanoma high Bak levels corresponded to improved survival (10-year survival of 62%), while low Bak correlated with low survival (10-year survival of 10%) (Fecker et al., 2006). Bax levels correlated in a similar way. |
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Entity | Autoimmune diseases |
Note | Severe autoimmune disease occurs in adult mice following deletion of both Bak and its close relative Bax (Takeuchi et al., 2005). The mice accumulate excess memory B- and T-cells in lymphoid and mesenchymal organs, leading to hepato-splenomegaly, lymphadenopathy, and thymic selection impairment. In humans, similar deletion of two copies of BAK1 (and BAX) does not occur, however less marked changes in Bak protein levels, as well as BAK1 mutations, have been associated with autoimmune disease in rare cases (see below). |
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Entity | Sjogren's syndrome |
Note | The Bak protein and its gene mutation may participate in the pathology and susceptibility of Sjogren's syndrome, as Bak was over-expressed in patient autoimmune lesions (Anaya et al., 2005). In a later study three polymorphisms in BAK1 were associated with Sjogren's syndrome (Delgado-Vega et al., 2009). |
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Entity | Coeliac disease |
Note | A significant increase in Bak mRNA and protein levels was found in the intestinal lesions of patients with untreated coeliac disease (Chernavsky et al., 2002). The increase in Bak and in apoptosis of enterocytes may be due to increased IFN-gamma signalling. |
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Entity | Graves' disease |
Note | Differential expression of Bak (and Bcl-2 and Bax) was associated with apoptosis in thyrocytes and lymphoid follicles, implicating Bak in the pathology of Grave's disease (Hiromatsu et al., 2004). |
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Entity | Multiple sclerosis |
Note | Bak mRNA levels were increased in the autoimmune lesions of patients with multiple sclerosis (Banisor and Kalman, 2004). |
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Entity | Ataxia telangiectasia |
Note | BAK1 mutations were observed in 8 of 50 patients with ataxia telangiectasia, and were each a silent mutation in exon 2 in codon 14 (TGC>TGT), while none of the healthy controls had such an alteration (Isaian et al., 2009). |
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Entity | Transient platelet loss |
Note | Bak can be activated to kill platelets as a side effect of new anti-cancer treatments (Mason et al., 2007; Oltersdorf et al., 2005). The small molecule ABT-737 is a BH3-mimetic that binds specifically to prosurvival proteins (Bcl-2, Bcl-xL, Bcl-w) that are commonly over-expressed in cancers. As platelets contain Bcl-xL as the predominant prosurvival protein guarding Bak, ABT-737 causes Bak activation and transient loss of platelets. |
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Entity | Age-related hearing loss |
Note | In mice, Bak-mediated apoptosis exacerbated age-related hearing loss (Someya et al., 2009; Someya et al., 2007). Moreover, hearing loss was decreased if Bak was deleted, if mice were kept on a calorie restriction diet, or given oral supplementation with antioxidants. In keeping with oxidative stress was proposed to induce Bak expression in primary cells from cochlear cells. |
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Entity | Aortic aneurysms |
Note | A possible role for Bak mutation in aortic aneurysms was evident in a study of 31 patients with abdominal aortic aneurysms (Gottlieb et al., 2009). Two single nucleotide polymorphisms (R42H and V52A) in the BAK1 gene were present in both diseased (31 cases) and healthy aortic tissue (5 cases), but not in matching blood samples. The authors propose that multiple variants of a gene such as BAK1 might pre-exist within disease-susceptible tissues, and can be selected for during disease progression. |
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