The Effects of Immunosuppressive Drugs on the Regulation of Activation-Induced Apoptotic Cell Death in Thymocytes

Sa, McCarthy; Rn, Cacchione; Ms, Mainwaring; Cairns, JS

doi:10.1097/00007890-199209000-00029

Cited by 44 publications

(18 citation statements)

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“…2B); furthermore, the extent of DNA fragmentation correlates well with the results in Fig. 2A (19,20,25 mice, global rather than sporadic nondeletion of "forbidden" TCR Vp subtypes would have been expected in these mice.…”

supporting

confidence: 83%

“…Irradiation was also tested over a wide dose range (162-2100 rads); control thymocytes were sensitive over the full range, whereas LST1135 thymocytes were resistant over the full range (data not shown). It should be noted that the dose response for A23187 plus PMA is quite complex and that other doses (i.e., A23187 at 100-125 ng/ml plus PMA at 10 ng/ml) induce a protective mechanism that inhibits apoptosis in normal control thymocytes (19,20).…”

mentioning

confidence: 99%

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Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53.

McCarthy

Symonds²,

Dyke³

1994

Proc. Natl. Acad. Sci. U.S.A.

103

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Several proteins encoded by DNA tumor viruses are thought to disrupt cellular growth control by interacting with key cellular proteins, such as p53 and pRB, that normally function to regulate cell growth. However, the biological consequences of intracellular complexing between the viral oncoproteins and cellular proteins have remained unclear. Such complexes could either facilitate functional inactivation of the cellular proteins, leading to a loss-of-function phenotype, or could activate new functions, leading to a gain-of-function phenotype. Here we demonstrate that the simian virus 40 large tumor (T) antigen produces a loss-ofp53-function phenotype when introduced into the thymocytes of transgenic mice. Like thymocytes from the recently characterized p53-null mice, thymocytes from transgenic mice expressing a T-antigen variant capable of binding to p53 are resistant to irradiation-induced apoptosis. Thymocytes from transgenic mice expressing a mutant T antigen that is unable to complex p53, but retains the ability to complex the pRB and p107 proteins, retain sensitivity to irradiation. We further demonstrate that although irradiation-induced apoptosis is impaired by T antigen, clonal deletion of autoreactive thymocytes via p53-independent apoptosis is not perturbed by T antigen. These results provide convincing evidence that T antigen inactivates p53 in thymocytes in vivo and suggest a mechanism by which T antigen predisposes thymocytes to tumorigenesis in T antigen-transgenic mice.The transforming proteins from at least three distinct DNA tumor viruses, adenovirus, simian virus 40 (SV40), and oncogenic human papillomaviruses (HPVs), interact with a common subset of cellular proteins to disrupt normal cellular growth regulation. At least two of these cellular proteins, pRB and p53, may function to negatively regulate cell growth and are often mutated in human tumors (see refs. 1-3 for review). These observations have led to the hypothesis that the ability of the DNA tumor virus proteins to stimulate cell growth reflects the release of a brake on cell proliferation normally imposed by proteins such as p53 and pRB (4).However, the specific biological consequences of each viral/ cellular protein interaction are poorly understood. Although inactivation of negative regulators is one possible route to the induction of tumorigenic changes, another possibility is that these protein interactions induce new dominant activities. This possibility is supported by the observation that certain mutant forms of p53 appear to have dominant oncogenic activities that are not obviously the result of transdominant inhibition of normal p53 function (1).The

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supporting

confidence: 83%

mentioning

confidence: 99%

Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53.

McCarthy

Symonds²,

Dyke³

1994

Proc. Natl. Acad. Sci. U.S.A.

103

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“…45 However, the ability of rapamycin to induce apoptosis is by no means universal (see e.g. Yao and Cooper, 46 McCarthy et al 47 and Staruch et al 48 ), although numerous studies have shown it can synergise with other to promote apoptosis. It may be that some types of transformed cells are particularly sensitive to the proapoptotic effects of rapamycin (see, e.g.…”

Section: Eif4e Apoptosis and Cell Transformationmentioning

confidence: 99%

The eukaryotic initiation factor 4E-binding proteins and apoptosis

Proud

2005

Cell Death Differ

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“…Rapamycin, an immunosuppressant blocked the activation of mTOR/p70S6K, thus compromising the cell's ability to progress through the G1 phase of the cell cycle (14,15). Rapamycin derivatives are in clinical trials for the treatment of several cancer types (16) although the induction of apoptosis by rapamycin is not universal (17,18). It has been reported that rapamycin can synergize with other agents such as tamoxifen, imanitib and doxorubicin to enhance apoptosis (19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Constitutive activation of p70 S6 kinase is associated with intrinsic resistance to cisplatin

Dhar¹,

Basu²

2008

Int J Oncol

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Abstract. Cisplatin is widely used for the treatment of solid tumors, including small cell lung cancers, but its success is often compromised due to relapse and resistance to further treatment. p70 ribosomal S6 kinase (p70S6K) has been shown to be upregulated in lung cancer cells. In the present study, we investigated whether the p70S6K pathway contributes to cisplatin resistance in human small cell lung cancer H69 cells. The levels of phosphorylated p70S6K and its downstream target S6 but not total p70S6K or S6 were elevated in the H69 cells that acquired resistance to cisplatin (H69/CP) compared to parental H69 cells. Cisplatin treatment resulted in the activation of p70S6K and downregulation of p70S6K was associated with cisplatin-induced PARP cleavage. While the ability of cisplatin to induce apoptosis was attenuated in H69/CP cells, inhibition of p70S6K by rapamycin enhanced cisplatin-induced apoptosis in these cells as evident by the increase in cisplatin-induced poly(ADP-ribose) polymerase (PARP) cleavage. The phosphoinositide 3-kinase (PI3K) inhibitor Ly294002 alone induced PARP cleavage and further augmented cisplatin-induced PARP cleavage. In contrast, inhibition of extracellular signal-regulated kinase (ERK) by U0126 attenuated cisplatin-induced PARP cleavage. Both rapamycin and Ly294002 enhanced cisplatin-induced activation of ERK1/2. Taken together, these results suggest that activation of p70S6K contributes to cisplatin resistance in small cell lung cancer H69 cells, and inhibition/downregulation of p70S6K as well as activation of ERK1/2 could circumvent cisplatin resistance.

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The Effects of Immunosuppressive Drugs on the Regulation of Activation-Induced Apoptotic Cell Death in Thymocytes

Cited by 44 publications

References 0 publications

Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53.

Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53.

The eukaryotic initiation factor 4E-binding proteins and apoptosis

Constitutive activation of p70 S6 kinase is associated with intrinsic resistance to cisplatin

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