Bcl-2 family proteins as targets for anticancer drug design

Huang, Ziwei

doi:10.1038/sj.onc.1204087

Cited by 184 publications

(125 citation statements)

References 30 publications

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“…36 Alternatively, Bcl-xL may regulate activation of caspase-8 which is bound to the outer mitochondrial membrane 40 or present inside the endoplasmic reticulum. 41 Altered Bcl-xL expression features in many diseases such as tumors, 42 disorders in the central nervous system, 43 and vascular diseases. 44 Specifically, Bcl-xL is overexpressed in many cancers, including different lymphomas in which it (1) increases survival of cancer cells, thus augmenting their invasive and metastatic abilities, and (2) determines resistance of cancer cells to chemotherapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

Decrease of Bcl-xL and augmentation of thymocyte apoptosis in GILZ overexpressing transgenic mice

Delfino

Agostini

Spinicelli

et al. 2004

Blood

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Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous genes. GILZ (glucocorticoidinduced leucine zipper), being one of them, is strongly up-regulated in the thymus. To elucidate its function we generated transgenic mice overexpressing it specifically in the T-cell lineage and characterized its influence on thymus function. In young adult transgenic mice CD4 ؉ CD8 ؉ thymocyte number was significantly decreased and ex vivo thymocyte apoptosis was increased. Apoptotic pathway analysis detected reduced antiapoptotic B-cell leukemia XL (Bcl-xL) expression and increased activation of caspase-8 and caspase-3. Time-course experiments showed that in wild-type (WT) thymocytes GILZ up-regulation was followed by sequential Bcl-xL decreased expression and activation of caspase-8 and of caspase-3. Moreover, GILZ delivered inside WT thymocytes by a fusion protein with the transactivator of transcription (TAT) peptide decreased Bcl-xL and promoted their apoptosis. In aged mice perturbation of thymic subset numbers was amplified over time, as demonstrated by a further decrease in CD4 ؉ CD8 ؉ cells and increases in CD4 ؉ CD8 ؊ , CD4 ؊ CD8 ؊ , and CD8 ؉ CD4 ؊ cell counts. These results support the hypothesis that GILZ participates in the regulation of thymocyte apoptosis by glucocorticoids. IntroductionGlucocorticoids (GCs) are hormones and drugs that express their functions by binding and activating their specific intracellular receptor (GR), thus acting through genomic and nongenomic mechanisms. The thymus, one of their target organs, promotes thymocyte maturation to functional CD4 ϩ or CD8 ϩ single positive (SP) T lymphocytes that are ready to migrate to the periphery. T-cell development in the thymus is ordered by sequential steps that involve waves of cell proliferation and apoptosis. Apoptosis is a key process in thymus physiology and is triggered in 3 well-known ways: (1) negative selection, involving 5% of all thymocytes, eliminates autoreactive T-cell clones at the level of CD4 ϩ CD8 ϩ double-positive (DP) cells; (2) death by neglect involves 90% of DP thymocytes that are neither positively nor negatively selected; and (3) stress-induced cell death. 1 GCs promote apoptosis of DP thymocytes 2 but are not involved in apoptosis by negative selection. 3 Their role in apoptosis by neglect is uncertain, but they certainly mediate stress-induced apoptosis. 1 The apoptotic signaling pathway triggered by the synthetic GC dexamethasone (DEX) in thymocytes has recently been clarified to some extent. The GC receptor coordinates activation of gene transcription and caspase-8, -9, and -3 in a sequence that leads to thymocyte apoptosis. [4][5][6][7] Additionally, GC-mediated thymic apoptosis is regulated by many different molecules, and the B-cell leukemia 2 (Bcl-2) family of proteins is a critical regulator of apoptosis. 8 The family is subdivided into antiapoptotic members such as Bcl-2 and Bcl-xL, and proapoptotic members such as Bcl-2-associated X protein (Bax) and BCL-2 homologous antagonist/killer (Ba...

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Section: Discussionmentioning

confidence: 99%

Decrease of Bcl-xL and augmentation of thymocyte apoptosis in GILZ overexpressing transgenic mice

Delfino

Agostini

Spinicelli

et al. 2004

Blood

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“…Bcl-xL has been shown to inhibit apoptosis induced by various cytotoxic stimuli [16], although the role of Bcl-xL in non-apoptotic cell death, including necrosis and autophagic cell death, is unclear [17][18][19]. In this study, we assessed the role of Bcl-xL overexpression in these two distinct modes of cell death induced by different doses of doxorubicin, apoptosis and cell death through mitotic catastrophe.…”

Section: Overexpression Of Bcl-xl In Huh-7 Cells Effectively Blocks Hmentioning

confidence: 99%

Bcl-xL blocks high dose doxorubicin-induced apoptosis but not low dose doxorubicin-induced cell death through mitotic catastrophe

Park

Kim

Eom

et al. 2007

Biochemical and Biophysical Research Communications

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“…1 Overexpression of antiapoptotic Bcl-2 family proteins occurs in many cancers, generating interest in these proteins as possible drug discovery targets. 2 A favored strategy for Bcl-2 antagonism is based on mimicking the actions of endogenous inhibitors that bind Bcl-2 and its relatives via BH3 domains (reviewed in Reed 3 and Huang 4 ). The BH3 domain is a protein interaction motif found in numerous proapoptotic members of the Bcl-2 family that consists of a B16-25 amino-acid amphipathic alphahelix.…”

mentioning

confidence: 99%