Regulation of Bcl2 phosphorylation by stress response kinase pathway.

Basu, Aruna; You, Sun-Ah; Haldar, Subrata

doi:10.3892/ijo.16.3.497

Cited by 27 publications

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“…Following treatment, total cellular proteins were extracted. After normalization for total protein content, the resulting lysates were subjected to SDS ± PAGE and immunoblotting (Basu and Haldar, 1998b). Equal protein loading was veri®ed routinely by Ponceau S staining of the nitrocellulose membrane.…”

Section: Methodsmentioning

confidence: 99%

2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells

et al. 2002

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Section: Methodsmentioning

confidence: 99%

2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells

et al. 2002

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“…31,60,61 Depending on the cell line, ERK was found to be activated, unchanged, or even inhibited. Moreover, neither inhibition nor activation of this pathway affected Bcl-2 phosphorylation.…”

Section: What Kinase Phosphorylates Bcl-2 In Mitotic Arrest?mentioning

confidence: 99%

Unwinding the loop of Bcl-2 phosphorylation

2001

Leukemia

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Recent evidence indicates that anti-apoptotic functions of Bcl-2 can be regulated by its phosphorylation. According to the 'mitotic arrest-induced' model, multi-site phosphorylation of the Bcl-2 loop domain is followed by cell death. In contrast, in cytokine-dependent cell lines, cytokines mediate phosphorylation of Bcl-2 on S70, preventing apoptosis. As discussed in this review, these models are not mutually exclusive but reflect different cellular contexts. During mitotic arrest, signal transduction is unique and is fundamentally different from classical mitogenic signaling, since the nucleus membrane is dissolved, gene expression is reduced, and numerous kinases and regulatory proteins are hyperphosphorylated. Hyperphosphorylation of Bcl-2 mediated by paclitaxel and other microtubuleactive drugs is strictly dependent on targeting microtubules that in turn cause mitotic arrest. In addition to serine-70 (S70), microtubule-active agents promote phosphorylation of S87 and threonine-69 (T69), inactivating Bcl-2. A major obstacle for identification of the mitotic Bcl-2 kinase(s) is that inhibition of putative kinase(s) by any means (dominant-negative mutants, antisense oligonucleotides, pharmacological agents) may arrest cycle, preventing mitosis and Bcl-2 phosphorylation. The role of Bcl-2 phosphorylation in cell death is discussed. Leukemia (2001) 15, 869-874.

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“…104 The role of p34 cdc2 kinase and the microtubule-associated protein (MAP) kinases that include extracellular signal-regulated protein kinases (ERKs), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38, in modulating Bcl-2 phosphorylation is still unclear and could depend on the cell type and the cytotoxic agent. [105][106][107] For example, a transient and early activation of JNK/SAPK rather than Raf-1 phosphorylation might account for Bcl-2 phosphorylation in K562 myelogenous leukemia cells exposed to the 2-methoxyestradiol that inhibits microtubule dynamics. 107 Whatever the pathway, phosphorylation/dephosphorylation of Bcl-2 appears to be a molecular marker of cell survival or death in response to microtubule damaging anticancer drugs (Figure 4).…”

Section: Bcl-2 Phosphorylationmentioning

confidence: 99%

“…Several signal transduction pathways could be involved in antimicrotubule agentmediated Bcl-2 phosphorylation. [102][103][104][105][106][107] One of these pathways involves Raf-1, 102 an ubiquitously expressed serine/threonine kinase which is activated in cells treated with paclitaxel and whose expression is decreased in cell lines resistant to this drug. Raf-1-mediated phosphorylation of Bcl-2 could involve induction of the cyclin-dependent kinase inhibitor p21 WAF1/CIP1 , either as a consequence of p53 induction or not.…”

Section: Bcl-2 Phosphorylationmentioning

confidence: 99%

“…[99][100][101][102][103][104][105][106][107] Bcl-2 phosphorylation is specifically induced by anticancer drugs that interact with monomeric tubulin and affect microtubule polymerization such as vinca alkaloids, and those that interact with polymerized tubulin and prevent depolymerization such as taxanes. 100,101 This effect is not seen with DNA damaging agents.…”

Section: Bcl-2 Phosphorylationmentioning

confidence: 99%

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Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies

et al. 2000

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Most chemotherapeutic drugs can induce tumor cell death by apoptosis. Analysis of the molecular mechanisms that regulate apoptosis has indicated that anticancer agents simultaneously activate several pathways that either positively or negatively regulate the death process. The main pathway from specific damage induced by the drug to apoptosis involves activation of caspases in the cytosol by pro-apoptotic molecules such as cytochrome c released from the mitochondrial intermembrane space. At least in some cell types, anticancer drugs also upregulate the expression of death receptors and sensitize tumor cells to their cognate ligands. The Fas-mediated pathway could contribute to the early steps of drug-induced apoptosis while sensitization to the cytokine TRAIL could be used to amplify the response to cytotoxic drugs. The Bcl-2 family of proteins, that includes anti-and pro-apoptotic molecules, regulates cell sensitivity mainly at the mitochondrial level. Anticancer drugs modulate their expression (eg through p53-dependent gene transcription), their activity (eg by phosphorylating Bcl-2) and their subcellular localization (eg by inducing the translocation of specific BH3-only pro-apoptotic proteins). Very early after interacting with tumor cells, anticancer drugs also activate lipid-dependent signaling pathways that either increase or decrease cell ability to die by apoptosis. In addition, cytotoxic agents can activate protective pathways that involve activation of NF B transcription factor, accumulation of heat shock proteins such as Hsp27 and activation of proteins involved in cell cycle regulation. This review discusses how modulation of the balance between noxious and protective signals that regulate drug-induced apoptosis could be used to improve the efficacy of current therapeutic regimens in hematological malignancies.

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Regulation of Bcl2 phosphorylation by stress response kinase pathway.

Cited by 27 publications

References 0 publications

2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells

2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells

Unwinding the loop of Bcl-2 phosphorylation

Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies

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