Expression of the bcl‐2 family of pro‐ and anti‐apoptotic genes in multiple myeloma and normal plasma cells

Spets, Helena; Strömberg, Thomas; Georgii-Hemming, Patrik; Siljason, Jan; Nilsson, Kenneth; Jernberg-Wiklund, Helena

doi:10.1034/j.1600-0609.2002.01549.x

Cited by 86 publications

(54 citation statements)

References 47 publications

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“…IL-6 and IL-6-regulated acute phase proteins were anti-inflammatory and immunosuppressive (40,46,48,51). Several reports showed that IL-6 prevented the death of cells exposed to hypoxia and LPS, and IL-6 and LPS treatment resulted in increased Bcl-2 gene expression (37,44,52). Our data demonstrated that protection from cell damage by FTS was associated with the induction of Bcl-2 mRNA in the pancreas.…”

Section: Discussionsupporting

confidence: 53%

Serum Thymic Factor Prevents LPS‐Induced Pancreatic Cell Damage in Mice via Up‐Regulation of Bcl‐2 Expression in Pancreas

Saitoh

Awaya

Sakudo

et al. 2004

Microbiology and Immunology

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The protective effect of synthetic serum thymic factor (FTS) nonapeptide on lipopolysaccharide (LPS)‐induced pancreatic cell damage in 10‐week‐old BALB/c male mice was investigated. Mice were divided into three groups. Group I was treated with LPS (10 μg/head; i.p.) (LPS‐treated mice). Group II was administered with FTS (50 μg/head; i.p.) 24 hr before treatment with LPS and complemented immediately before LPS injection with FTS (50 μg/head; i.p.) (FTS‐administered mice). Group III was only treated with the same volume of saline (control mice). Treatment of LPS in vivo resulted in the destruction of pancreatic acinar cells. In those cells, many apoptotic cells were detected by immunohistochemistry using an anti‐single stranded DNA antibody. Immunohistochemistry and reverse transcription‐polymerase chain reaction (RT‐PCR) revealed that LPS treatment also caused low or a lack of insulin expression in pancreatic islets. In contrast, morphological change was not seen and apoptotic cell death was suppressed in pancreatic cells of FTS‐administered mice. Moreover, insulin expression was normal in those mice. FTS administration enhanced expression of Bcl‐2 mRNA levels in pancreatic tissues and IL‐6 mRNA levels in splenocytes significantly compared with those of LPS treatment at 3 hr after LPS injection. These findings suggest that FTS prevents LPS‐induced cell damage via enhancing Bcl‐2 expression in the pancreas and systemic IL‐6 production.

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Section: Discussionsupporting

confidence: 53%

Serum Thymic Factor Prevents LPS‐Induced Pancreatic Cell Damage in Mice via Up‐Regulation of Bcl‐2 Expression in Pancreas

Saitoh

Awaya

Sakudo

et al. 2004

Microbiology and Immunology

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“…The expression pattern of the Bcl-2 family separates the malignant phenotype of MM from normal plasma cells. In MM there is higher expression of the antiapoptotic Bcl-2 and Mcl-1 but not of Bcl-xL, and there is a lower level of expression of Bax [29]. On the other hand, targeted overexpression of Bcl-xL and c-Myc in B-lymphoid cells in mice resulted in lymphoproliferative disease and plasma cell malignancies.…”

Section: Bcl-2 Proteins Are Key Targets Of Therapeuticsmentioning

confidence: 99%

Apoptosis of Multiple Myeloma

Oancea

Mani²,

Hussein³

et al. 2004

International Journal of Hematology

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Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells. MM cells localize to the bone marrow, where cell adhesion-mediated autocrine or paracrine activation of various cytokines, such as interleukin 6, insulin-like growth factor 1, and interferon α, results in their accumulation mainly because of loss of critical apoptotic controls. Resistance to apoptosis, a genetically regulated cell death process, may play a critical role in both pathogenesis and resistance to treatment of MM. Abnormalities in regulation and execution of apoptosis can contribute to tumor initiation, progression, as well as to tumor resistance to various therapeutic agents. Apoptosis is executed via 2 main pathways that lead to activation of caspases: the death receptor (extrinsic) pathway and the mitochondrial (intrinsic) pathway. Ionizing radiation and chemotherapeutic agents act primarily through the intrinsic pathway, in which mitochondria play the central role. Various therapeutic modalities that are effective in MM modulate levels of the proapoptotic and antiapoptotic Bcl-2 family of proteins and of inhibitors of apoptosis, expression of which is primarily regulated by p53, nuclear factor κB, and STAT (signal transducers and activators of transcription) factors. This review focuses on the key concepts and some of the most recent studies of signaling pathways regulated in MM and summarizes what is known about the clinical role of these pathways.

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“…Mcl-1 is highly expressed in some malignant B-cells (Ghia et al, 1998;Kitada et al, 1998;Soini et al, 1998;Agarwal and Naresh, 2002;Pagnano et al, 2002;Spets et al, 2002;Khoury et al, 2003), and this can correlate with clinical behaviour, such as failure to obtain complete remission in chronic lymphocytic leukemia (CLL) (Kitada et al, 1998). Importantly, enforced expression of Mcl-1 in transgenic mice promotes lymphomagenesis with a higher probability than Bcl-2 (approx.…”

Section: Introductionmentioning

confidence: 99%

Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage

et al. 2004

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Enforced expression of the antiapoptotic Bcl-2 family protein Mcl-1 promotes lymphomagenesis in the mouse; however, the functional role of Mcl-1 in human B-cell lymphoma remains unclear. We demonstrate that Mcl-1 is widely expressed in malignant B-cells, and high-level expression of Mcl-1 is required for B-lymphoma cell survival, since transfection of Mcl-1-specific antisense oligodeoxynucleotides was sufficient to promote apoptosis in Akata6 lymphoma cells. Mcl-1 was efficiently cleaved by caspases at evolutionarily conserved aspartic acid residues in vitro, and during cisplatin-induced apoptosis in B-lymphoma cell lines and spontaneous apoptosis of primary malignant B-cells. Overexpression of the Mcl-1 cleavage product that accumulated during apoptosis was sufficient to kill cells. Therefore, Mcl-1 is an essential survival molecule for B-lymphoma cells and is cleaved by caspases to a death-promoting molecule during apoptosis. In contrast to Mcl-1, Bcl-2 and Bcl-X L were relatively resistant to caspase cleavage in vitro and in intact cells. Interfering with Mcl-1 function appears to be an effective means of inducing apoptosis in Mcl-1-positive B-cell lymphoma, and the unique sensitivity of Mcl-1 to caspasemediated cleavage suggests an attractive strategy for converting it to a proapoptotic molecule.

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Expression of the bcl‐2 family of pro‐ and anti‐apoptotic genes in multiple myeloma and normal plasma cells

Cited by 86 publications

References 47 publications

Serum Thymic Factor Prevents LPS‐Induced Pancreatic Cell Damage in Mice via Up‐Regulation of Bcl‐2 Expression in Pancreas

Serum Thymic Factor Prevents LPS‐Induced Pancreatic Cell Damage in Mice via Up‐Regulation of Bcl‐2 Expression in Pancreas

Apoptosis of Multiple Myeloma

Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage

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