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[Cancer Research 60, 1217-1220, March 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

CD95 (Fas/APO-1) and p53 Signal Apoptosis Independently in Diverse Cell Types1

Liam O’Connor, Alan W. Harris and Andreas Strasser2

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
The tumor suppressor p53 exerts its antioncogenic effects in cells chiefly by regulating their progression through the cell cycle and by inducing cell death. It has been claimed that p53-transduced apoptosis involves the death receptor CD95 (Fas/APO-1). We report that thymocytes from mice lacking functional Fas ligand (gld) show normal sensitivity to apoptosis transduced by p53, and that hepatocytes from p53-/- mice have normal sensitivity to apoptosis triggered through ligation of CD95. p53 and CD95, therefore, function in independent pathways to cell death in these diverse cell types.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The tumor suppressor p53 exerts its antioncogenic potential in cells chiefly by managing their responses to stress (1 , 2) . When cells are exposed to DNA-damaging agents, p53 levels rise, attributable at least in part to increased stability of the protein (3, 4, 5, 6) , and posttranslational changes cause an increase in p53 transcription factor activity (7) . This increase in p53 activity leads to induction of genes that control cell cycle arrest and apoptosis. For instance, the p53 gene is essential for DNA damage-induced cell cycle arrest in fibroblasts and apoptosis in lymphoid cells (8, 9, 10) .

Exactly how p53 triggers apoptosis is unclear, but it has been reported to involve both transcription-dependent and -independent mechanisms. One study reported that increased levels of p53 induced apoptosis through transcriptional activation of proapoptotic genes such as bax (11) . Induction of bax, however, is not sufficient for p53-transduced apoptosis, because expression of a bax transgene does not restore DNA damage-induced apoptosis in p53-/- thymocytes (12) . p53-induced apoptosis has been reported to be dependent on transcription (13) , but there have also been reports that p53 can induce apoptosis without new RNA or protein synthesis (1 , 2) . A possible mechanism for this has been suggested by recent reports that p53 can trigger apoptosis through CD95, a member of the tumor necrosis factor superfamily of cell surface receptors (14) . Overexpression of p53 in transformed cell lines has been reported to result in increased cell surface expression of CD95 and subsequent apoptosis (15 , 16) . Other studies, however, have suggested there is no link between p53 and CD95 in signaling apoptosis. Cell lines with inactive p53 have been shown to have equivalent sensitivity to CD95-triggered apoptosis to cells with wild-type p53 (17) .

We believe any physiological significance of cross-talk between CD95 and p53 in signaling apoptosis is best established by comparing animals that express these molecules at normal levels and mutant animals that lack them altogether. We report that cells from mice lacking functional Fas ligand (gld) show normal sensitivity to apoptosis caused by DNA-damaging agents, and that cells from p53-/- mice have normal sensitivity to apoptosis triggered by ligation of CD95. p53 and CD95, therefore, function in independent pathways to cell death in the cell types studied.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Induction of Apoptosis in Tissue Culture.
The derivation of p53-/- (18) , gld, and lpr (19) mice have been described. These strains had been backcrossed with normal C57BL/6J mice for six or more generations. The procedures for culture of primary cells are described elsewhere (20) . Thymocytes were cultured in the presence of a range of concentrations of dexamethasone (0.01–1.0 µM) or etoposide (0.1–10 µg/ml) or subjected to 2.5–10 Gy {gamma}-irradiation from a 60Co source. Samples were taken at various times after this treatment, and cell viability was determined by flow cytometric analysis of propidium iodide (2 µg/ml)-stained cells using a FACScan (Becton Dickinson).

Immunofluorescence Staining for Detection of CD95 Expression.
Liver samples were fixed in 2% paraformaldehyde and then sections were cut and embedded in wax. After blocking of endogenous Fc receptors with normal mouse serum, the sections were incubated serially with monoclonal hamster anti-Fas (Jo2) antibody (2.5 µg/ml), followed by FITC-conjugated mouse antihamster IgG antibody (2.5 µg/ml; PharMingen). CD95 expression on thymocytes was detected using a similar staining protocol.

Induction of Apoptosis through CD95 in Vivo.
A range of doses of Jo2 anti-CD95 monoclonal antibody was injected in 100 µl of saline into the tail vein of mice 8–14 weeks of age. The mice were killed after 2 h, and then liver and blood samples were taken for analysis.

Detection of Apoptotic Cells by TUNEL.3
Liver sections were treated with 20 µg/ml proteinase K for 15 min at 22°C, and then DNA free ends were labeled with dUTP-biotin (Roche Diagnostics) using terminal deoxynucleotidyl transferase (Promega Corp.; Ref. 21 ) and revealed with avidin-biotinylated horseradish peroxidase and diaminobenzidine. TUNEL-labeled nuclei were counted in 15 or more 0.56-mm2 fields.

Liver Enzyme Assays.
Blood samples were taken 2 h after injection of Jo2 anti-Fas antibody. ALP, ALT, and AST activity in serum were measured on a CX3 automatic analyzer (Beckman).


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Functional FasL Expression Is Not Needed for DNA Damage-induced Apoptosis.
We isolated thymocytes from gld and control mice and examined their cell surface expression of CD95 and sensitivity to various apoptotic stimuli. Thymocytes from gld mice had normal cell surface levels of CD95 (Fig. 1A)Citation and showed normal responses to a range of doses of the glucocorticoid dexamethasone, the topoisomerase inhibitor etoposide, and {gamma}-irradiation (Fig. 1BCitation , upper panels). gld thymocytes also died at equivalent rates to control cells when exposed to these apoptotic stimuli over 48 h (Fig. 1BCitation , lower panels). These results show that thymocytes from mice lacking functional FasL (gld) are unaffected in their response to p53-transduced apoptotic stimuli, such as those elicited by genotoxic stress, suggesting that FasL plays no role in p53-transduced apoptosis.



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  		Fig. 1. Apoptosis caused by DNA damage is normal in thymocytes from gld mice. A, CD95 expression on gld and control thymocytes was determined by immunofluorescence staining and flow cytometric analysis. B, apoptosis in gld and control thymocyte cultures exposed to various cytotoxic treatments. Upper panels, dose response at 24 h. Lower panels, time course with dexamethasone (0.1 µM), etoposide (10 µg/ml), and {gamma}-irradiation (5 Gy).

 
CD95-induced Apoptosis Proceeds Independently of p53 Expression.
We isolated thymocytes from p53-/- and control mice and examined their CD95 expression and sensitivity to CD95-induced apoptosis. Thymocytes isolated from p53-/- mice showed equivalent cell surface expression of CD95 to control thymocytes (Fig. 2A)Citation and equivalent sensitivity to a range of doses of monoclonal Jo2 anti-CD95 antibody and at various time points up to 48 h after administration (Fig. 2BCitation and not shown).



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  		Fig. 2. Apoptosis triggered through CD95 is normal in p53-/- thymocytes. A, CD95 expression on p53-/- and control thymocytes was determined by immunofluorescence staining and flow cytometric analysis. B, apoptosis in p53-/- and control thymocyte cultures treated with a range of doses of Jo2 anti-CD95 antibody. Bars, SD.

 
We also decided to test the role of p53 in CD95-induced apoptosis in whole animals. We injected groups of p53-/- and control mice with a range of doses of Jo2 anti-CD95 antibody and examined their liver for CD95 expression and apoptosis. Immunostaining of liver sections from both groups of mice showed equivalent levels of CD95 expression (Fig. 3A)Citation . We then examined apoptosis in liver sections by TUNEL staining (Fig. 3B)Citation . Quantitation of TUNEL-positive cells in liver sections from mice treated with varying doses of Jo2 anti-CD95 antibody showed no difference between p53-/- and control mice (Fig. 3C)Citation . We also measured the serum levels of enzymes known to be released as a result of hepatocyte destruction (22) . p53-/- and control mice had equivalent levels of ALP, ALT, and AST in their serum after administration of Jo2 anti-CD95 antibody (Fig. 4)Citation . Cell surface CD95 levels, CD95-induced apoptosis, and liver damage enzymes induced by Jo2 anti-CD95 antibody administration were all unaffected in mice lacking p53, suggesting that p53 does not play a role in CD95-induced apoptosis.



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  		Fig. 3. Liver apoptosis caused by injection of anti-CD95 antibody is normal in p53-/- mice. A, CD95 expression in liver sections from lpr, control, and p53-/- mice was determined by immunofluorescence staining. B, TUNEL staining of p53-/- and control liver sections from mice injected with 100 µg of Jo2 anti-CD95 antibody. C, apoptosis in liver sections from p53-/- and control mice injected with a range of doses of Jo2 anti-CD95 antibody. Bars, SD.

 


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  		Fig. 4. Acute liver damage caused by injection of Jo2 anti-CD95 antibody in normal and in p53-/- mice. ALP, ALT, and AST levels in serum from p53-/- and control mice after injection with Jo2 anti-CD95 antibody. Bars, SD.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
We have investigated whether apoptosis transduced by p53 and apoptosis triggered through the death receptor CD95 are linked in vivo. A mechanistic link between p53 and CD95 in signaling apoptosis can exist as one of two possibilities: either p53 activation results in CD95-transduced apoptosis, i.e., p53 is upstream of CD95, or intracellular events after cross-linking of CD95 on cell surfaces are somehow transduced by activated p53, i.e., CD95 is upstream of p53.

If p53 is upstream of CD95, the mechanism does not appear to be a simple effect of p53 on basal CD95 expression, because CD95 levels were normal in animals lacking p53 (Figs. 2ACitation and 3A)Citation . CD95 may be involved in p53-transduced apoptosis through, for instance, increased expression of CD95 after activation of p53. If this is the case, animals in which the CD95/CD95L system is disrupted should show an impaired response to p53-dependent apoptotic stimuli. It has already been established that mice that lack CD95 (lpr) have unimpaired p53-transduced apoptosis (20 , 23) , and the results presented here show that thymocytes from mice lacking functional CD95L are similarly unaffected (Fig. 1)Citation . It is also unlikely that other members of the tumor necrosis factor receptor family of death receptors are involved in signaling p53-transduced apoptosis. Cells expressing a dominant-negative form of the death adapter molecule FADD (also called MORT-1) or the caspase inhibitor crmA, which block all death receptor-induced apoptosis, have unimpaired responses to p53-transduced apoptosis (24 , 25) .

The second possibility is that CD95 is upstream of p53. Apoptosis pathways triggered through CD95 and related death receptors have been characterized extensively (14 , 26) . After cross-linking of CD95 on the cell surface, the intracellular region of CD95 recruits the adapter molecule FADD/MORT-1, which then recruits procaspase-8, resulting in its autocatalytic activation. This starts the proteolytic avalanche that leads to apoptosis. This model leaves no obvious place for p53 to exert an effect once apoptosis has been triggered through CD95. Nevertheless, if there were some unknown mechanism, animals lacking p53 should have impaired CD95-transduced apoptosis. When mice lacking p53 were injected with Jo2 anti-CD95 antibody, the ensuing hepatocyte apoptosis was indistinguishable from that found in control mice (Figs. 2Citation 3Citation 4)Citation ; therefore, p53 cannot play a role in CD95-transduced apoptosis in hepatocytes. This finding is consistent with results from a study of transformed cell lines, in which CD95-transduced apoptosis was unaffected by the status of their p53 genes (17) , and with a study showing that thymocytes from p53-/- mice were normally sensitive to anti-CD95 antibody (23) . Studies in cells from mutant mice have shown that absence of either Apaf-1 or caspase-9 substitutes for p53 loss in promoting oncogenesis (27) , which suggests that Apaf-1 and caspase-9 are in the apoptotic pathway triggered by p53. CD95-triggered apoptosis is unaffected in cells from either Apaf-1 or caspase-9 null mice, however (28, 29, 30, 31) . These results provide further evidence that CD95 and p53 signal apoptosis independently.

Why have other studies shown a link between p53 and CD95 in signaling apoptosis when our data suggest there is none? One explanation is that previous studies were performed in cell lines in which p53 was overexpressed at levels far in excess of those found in normal cells, even after genotoxic stress. Moreover, such lines are likely to already have aberrant apoptotic responses as a result of the transformation process, and many will also have lost endogenous p53 function. We believe studies based on extreme overexpression should always be viewed in the light of experiments performed under physiological conditions. There also exists the possibility that we have been selective in only studying thymocytes and hepatocytes, and that a link between p53 and CD95 in apoptosis signaling may exist in other cell types. However, the well-documented role of p53 and CD95 in lymphocyte apoptosis and the observation that animals injected with anti-CD95 antibody die from acute liver failure (22 , 26) mean that the cell types studied are among the most physiologically important.

The p53 gene is deleted or inactivated in about 50% of human tumors (1) . Understanding how p53 triggers apoptosis is therefore central to understanding how these tumors develop. CD95 has been suggested as a possible player in p53-transduced apoptosis (15 , 16) . It has even been proposed that loss of p53 in tumors may allow increased survival because of loss of CD95-induced apoptosis, and CD95 is therefore a potential target for therapy of such tumors (32) . Our data, from non-transformed cells in whole animals and in tissue culture, strongly suggest that pathways to apoptosis that are activated through p53 are distinct from those triggered by CD95.


   ACKNOWLEDGMENTS
 
We thank D. Huang and K. Newton for comments on the manuscript, S. Nagata for kindly providing Jo2 monoclonal antibody, D. Deam for serum enzyme assays, W. Heath for providing gld mice, J. Merryful for expert animal husbandry, L. Cullen for mouse genotyping, and S. Mihajlovic for preparing histological sections.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by the Josef Steiner Cancer Foundation, the National Health and Medical Research Council, Canberra, and the Anti-Cancer Council of Victoria. L. O. was supported by an Edith Moffatt Postgraduate Scholarship and an Anti-Cancer Council of Victoria Postdoctoral Fellowship. Back

2 To whom requests for reprints should be addressed, at The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia. Phone: 61-3-9345-2624; Fax: 61-3-9347-0852; E-mail: strasser{at}wehi.edu.au Back

3 The abbreviations used are: TUNEL, terminal deoxynucleotidyl transferase-mediated nick end labeling; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FasL, Fas ligand. Back

Received 10/ 7/99. Accepted 1/18/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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