Ionizing radiation stimulates unidentified tyrosine-specific protein kinases in human B-lymphocyte precursors, triggering apoptosis and clonogenic cell death.

Uckun, Fatih M.; Tuel‐Ahlgren, Lisa; Song, Chang W.; Waddick, Kevin G.; Myers, Dorothea E.; Kirihara, Jean M.; Ledbetter, Jeffrey A.; Schieven, Gary L.

doi:10.1073/pnas.89.19.9005

Cited by 173 publications

(95 citation statements)

References 13 publications

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“…Mounting evidences have indicated that changes in the phosphorylation state of proteins are important during PCD induced by different agents in higher eucaryotes. 28 Altogether, these observations and our present studies indicate that alterations of the phosphorylation state of cytosolic proteins like PKC can efficiently trigger PCD in a wide range of cell systems from higher eucaryotes to lower unicellular eucaryotes.…”

Section: Discussionsupporting

confidence: 76%

Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I–DNA complex

et al. 2006

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Protein kinase C (PKC) is an important constituent of the signaling pathways involved in apoptosis. We report here that like staurosporine, withaferin A is a potent inhibitor of PKC. In Leishmania donovani, the inhibition of PKC by withaferin A causes depolarization of DW m and generates ROS inside cells. Loss of DW m leads to the release of cytochrome c into the cytosol and subsequently activates caspase-like proteases and oligonucleosomal DNA cleavage. Moreover, in treated cells, oxidative DNA lesions facilitate the stabilization of topoisomerase I-mediated cleavable complexes, which also contribute to DNA fragmentation. However, withaferin A and staurosporine cannot induce cleavable complex formation in vitro with recombinant topoisomerase I nor with nuclear extracts from control cells. Taken together, our results indicate that inhibition of PKC by withaferin A is a central event for the induction of apoptosis and that the stabilization of topoisomerase I-DNA complex is necessary to amplify apoptotic process.

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Section: Discussionsupporting

confidence: 76%

Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I–DNA complex

et al. 2006

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“…Apoptosis induction in U937 cells was also abrogated by HMA (Ginestier-Verne et al, 1996). PTKs have been implicated in the triggering of apoptosis in some cellular contexts (Carson et al, 1994;Bergamaschi et al, 1993;Uckun et al, 1992;Uckun et al, 1996) while promoting survival in others (Bedi et al, 1994;McGahon et al, 1994;Zhu et al, 1996). It is therefore plausible that an HMA-sensitive PTK is part of the signalling pathway which induces apoptosis in HL60 and U937 cells following etoposide treatment.…”

Section: Discussionmentioning

confidence: 99%

Herbimycin A accelerates the induction of apoptosis following etoposide treatment or γ-irradiation of bcr/abl-positive leukaemia cells

et al. 1998

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Philadelphia chromosome (Ph)-positive leukaemia cells express the chimeric bcr/abl oncoprotein, whose deregulated protein tyrosine kinase (PTK) activity antagonizes the induction of apoptosis by DNA damaging agents. Treatment of Ph-positive K562, TOM 1 and KCL-22 cells with etoposide for 2d induced cytosolic vacuolation, but not nuclear condensation or DNA fragmentation. The bcr/abl kinase-selective inhibitor herbimycin A increased the induction of nuclear apoptosis by etoposide or g-radiation. The concentration of herbimycin required to synergize with etoposide was similar to that required to decrease the level of tyrosine phosphorylated proteins or of the protein tyrosine kinase activity of anti-abl immune complexes in K562 cells. The ability of herbimycin A to sensitize K562, TOM 1 or KCL-22 cells to apoptosis induction correlated with its ability to decrease the cellular content of phosphotyrosyl proteins in these Philadelphia-positive lines. Enhancement of nuclear apoptosis by herbimycin was not attributable to downregulation of the bcl-2 or bcl-X L anti-apoptotic proteins. In contrast, herbimycin protected Philadelphianegative HL60 cells from apoptosis induction by etoposide and did not a ect killing of NC37 and CEM cells. The data suggest that the induction of apoptosis is blocked in cells expressing the bcr/abl oncoprotein and that herbimycin A increases induction of programmed cell death following DNA damage. Selective PTK inhibitors may therefore be of value in securing the genetic death of Ph-positive leukaemia cells.

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“…However, current evidence indicates epigenetic mechanisms are induced by these agents. Ultraviolet ionizing radiation and chemical mutagens and carcinogens can induce gene expression (8,(31)(32)(33)(34)(35), modulate cell-cell communication (36,37), cause apoptosis without DNA damage (38), and effect transformation in vitro (39) (47).…”

mentioning

confidence: 99%

Hierarchical and cybernetic nature of biologic systems and their relevance to homeostatic adaptation to low-level exposures to oxidative stress-inducing agents.

Trosko

1998

Environ Health Perspect

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During evolution in an aerobic environment, multicellular organisms survived by adaptive responses to both the endogenous oxidative metabolism in the cells of the organism and the chemicals and low-level radiation to which they had been exposed. The defense repertoire exists at all levels of the biological hierarchy-from the molecular and biochemical level to the cellular and tissue level to the organ and organ system level. Cells contain preventive antioxidants to suppress oxidative damage to membranes. Cells also contain proteins and DNA; built-in redundancies for damaged molecules and organelles; tightly coupled redox systems; pools of reductants; antioxidants; DNA repair mechanisms and sensitive sensor molecules such as nuclear factor kappa beta; and signal transduction mechanisms affecting both transcription and post-translational modification of proteins needed to cope with oxidative stress. The biologic consequences of the low-level radiation that exceeds the background level of oxidative damage could be necrosis or apoptosis, cell proliferation, or cell differentiation. These effects are triggered by oxidative stress-induced signal transduction mechanisms-an epigenetic, not genotoxic, process. If the end points of cell proliferation, differentiation, or cell death are not seen at frequencies above background levels in an organism, it is unlikely that low-level radiation would play a role in the multistep processes of chronic diseases such as cancer. The mechanism linked to homeostatic regulation of proliferation and adaptive functions in a multicellular organism could provide protection of any one cell receiving deposited energy by the radiation tract through the sharing of reductants and by triggering apoptosis of target stem cells. Examples of the role of gap junctional intercellular communication in the adaptive response of cells and the bystander effect illustrate how the interaction of cells can modulate the effect of radiation on the single cell.

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Ionizing radiation stimulates unidentified tyrosine-specific protein kinases in human B-lymphocyte precursors, triggering apoptosis and clonogenic cell death.

Cited by 173 publications

References 13 publications

Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I–DNA complex

Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I–DNA complex

Herbimycin A accelerates the induction of apoptosis following etoposide treatment or γ-irradiation of bcr/abl-positive leukaemia cells

Hierarchical and cybernetic nature of biologic systems and their relevance to homeostatic adaptation to low-level exposures to oxidative stress-inducing agents.

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