bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship

Strasser, Andreas; Harris, Alan W.; Cory, Suzanne

doi:10.1016/0092-8674(91)90362-3

Cited by 1,008 publications

(775 citation statements)

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“…The role of the BCL-2-regulated apoptotic pathway in the response to anticancer therapeutics was first demonstrated when it was found that non-transformed lymphoid cells from Bcl-2 transgenic mice 132 and BCL-2-overexpressing lymphoma cells 133 were profoundly resistant to γ-irradiation, DNA damage-inducing chemotherapeutic drugs (e.g., etoposide) and glucocorticoids (e.g., dexamethasone). Similar protection from chemotherapeutic drug-induced apoptosis can be afforded by overexpression of any of the other prosurvival BCL-2 family members.…”

Section: The Role Of the Bcl-2-regulated Apoptotic Pathway In Cancer mentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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Section: The Role Of the Bcl-2-regulated Apoptotic Pathway In Cancer mentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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“…Bcl-2 can also protect against some forms of necrotic cell death. 45,46 The BCL2 protein is expressed in many different tissues. BCL2 is expressed in early hematopoietic progenitor cells of all lineages.…”

Section: Bcl-2 a New Type Of Oncogenementioning

confidence: 99%

t(14;18), a journey to eternity

Meijerink

1997

Leukemia

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The t(14;18) is the most frequent chromosomal aberration observed in follicular non-Hodgkin's lymphoma (NHL), and less frequently in diffuse large cell lymphoma (DLCL). The t(14;18) does not affect overall survival in follicular NHL or DLCL. It provides a unique lymphoma-specific marker that can be used to quantify residual disease during treatment, and may forward evaluation of new treatment protocols. The t(14;18) results in the deregulation of bcl-2, a proto-oncogene that protects against induction of programmed cell death (PCD). Nowadays, a whole family of bcl-2-related genes has been identified and consist of members which can either protect or promote induction of PCD. The family members form protein dimers, and the relative abundance of specific dimers regulates the cellular sensitivity to death signals (the rheostat model). Aberrant expression of different family members in several types of malignancies alter the cellular rheostat and thereby promote cellular resistance to chemotherapy.

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“…FITC-or phycoerythrinconjugated monoclonal antibodies against CD4, CD8, B220 (CD45R), and IgM were obtained from Pharmingen. Other antibodies (Thy-1 and CD45) were prepared and used as previously described (Strasser et al, 1991). Dead cells were excluded from analysis by co-staining with propidium iodide (1 mg/ml, Sigma, St Louis, MO).…”

Section: Flow Cytometrymentioning

confidence: 99%