Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 731-734
REVIEW ARTICLE
Role of Calcium in Glucocorticosteroid-Induced Apoptosis of
Thymocytes and Lymphoma Cells: Resurrection of Old Theories by New
Findings
By
Clark W. Distelhorst and
George Dubyak
From the Departments of Medicine, Pharmacology, and Physiology and
Biophysics, Case Western Reserve University, Cleveland, OH.
 |
INTRODUCTION |
MORE THAN 50 years ago, investigators
observed that the thymus gland undergoes hypertrophy in association
with adrenocortical insufficiency and atrophy in association with
adrenocortical excess.1,2 These observations led to the
realization that adrenal corticosteroids (ACS) have a "lympholytic
effect," which in turn stimulated clinical investigators to treat
lymphomas with ACS for the first time in the late 1940s.3,4
Today, we know that ACS do not directly lyse thymocytes and lymphoma
cells, but rather induce apoptosis.5 Apoptosis, or
programmed cell death, is a genetically regulated process in which the
cell is active in producing its own death, a type of cellular suicide
for the sake of maintaining homeostasis in the cellular
community.6-8
Although our understanding of apoptosis has advanced tremendously in
recent years, the mechanism by which ACS induce apoptosis in thymocytes
and lymphoma cells is not completely understood. In the 1970s, Sibley
and Tompkins determined that the initial step in ACS-induced apoptosis
is mediated through the ACS receptor and requires translocation of the
receptor from the cytoplasm into the nucleus.9 In the
nucleus, the ACS receptor functions as a transcription factor,
enhancing or repressing the expression of a selected repertoire of
genes.10 ACS may repress expression of genes necessary for
cell survival by attenuating AP-1 (c-Fos/c-Jun) transcription factor
activity,11 or may induce the transcription of genes
involved in carrying out the death program. The evidence in support of
the latter concept is twofold: first, inhibitors of RNA and protein
synthesis inhibit ACS-induced apoptosis12,13; and second,
the transactivation domain of the ACS receptor is required for
apoptosis induction by ACS.14
Progress in identifying ACS-inducible genes that mediate apoptosis had
been slow. Now, in the past year, two ACS-inducible genes have been
formally implicated in mediating apoptosis. One of the genes encodes a
purinergic receptor, P2X1, that functions as an ATP-gated
calcium channel,15 whereas the other gene encodes an
inositol 1,4,5-trisphosphate receptor (IP3R) that functions as an IP3-gated calcium channel.16 The fact
that both of these genes encode calcium channels has reawakened
interest in the role of calcium, a major intracellular second messenger
molecule, as a mediator of apoptosis. In this review, we first
summarize the evidence for involvement of these genes in apoptosis.
Then, we attempt to integrate these novel findings with previous
experimental evidence suggesting a role for calcium in signaling
glucocorticoid-induced apoptosis in both thymocytes and lymphoma cells.
| |
P2X1 RECEPTORS AND APOPTOSIS |
Recognition that purinergic receptors are involved in ACS-induced
apoptosis evolved out of an effort by Owens et al17 to identify differentially expressed mRNAs associated with
ACS-induced apoptosis in thymocytes. One of the differentially
expressed mRNAs identified by these investigators, termed RP-2, was
induced early in the course of ACS-induced apoptosis. However, the
identity of the RP-2 sequence was not elucidated until 5 years later,
when it was discovered that RP-2 corresponds to a partial sequence of a
gene encoding an ATP-gated cation channel, termed purinergic receptor or P2X receptor.18,19 This discovery
is particularly intriguing, because extracellular ATP has been
reported to induce apoptosis in thymocytes by increasing the
intracellular concentration of calcium.20,21
The P2X receptors constitute a family of at least seven
members, distributed throughout central and peripheral neurons, smooth muscles, epithelia, developing skeletal neuromuscular junctions, lymphocytes, platelets, and macrophages. P2X receptors are
nonselective cation channels with significant permeability to calcium.
P2X receptors engage in intercellular communication by
detecting the regulated (synaptic) or lytic (cell death) release of
intracellular metabolites such as ATP. Unlike other well-known ion
channels gated by extracellular ligands (eg, nicotinic, serotonin,
5-HT3), P2X receptors are characterized by
only two transmembrane domains with intracellular amino- and
carboxy-termini.22 RP-2 corresponds to the subfamily member
P2X1 (originally termed P2XR1), recently cloned
from vas deferens and PC12 cells.18,19 Curiously,
P2X receptors are structurally similar to some of the
Caenorhabditis elegans gene products implicated in
neuronal cell selection and death.
The link between P2X1 receptor expression and ACS-induced
apoptosis in rat thymocytes was recently established by Chvatchko et
al.15 These investigators found that P2X1
receptors were upregulated in thymocytes during ACS-induced apoptosis.
Furthermore, extracellular ATP enhanced ACS-induced apoptosis and
antagonists of ATP substantially reduced ACS-induced apoptosis,
suggesting that ACS-induced apoptosis is dependent on P2X1
receptor activation by extracellular ATP.
| |
IP3R AND APOPTOSIS |
The other ACS-inducible gene implicated in mediating apoptosis of both
thymocytes and lymphoma cells encodes the Type 3 IP3R.16 The IP3R has been
extensively characterized and plays a central role in calcium
signaling.23,24 Typically, IP3 generated in response to G-protein-coupled receptors and receptor tyrosine kinases binds to the IP3 receptor that spans
the endoplasmic reticulum (ER) membrane.23,24 The binding
of IP3 induces transient opening of the receptor, allowing
calcium to flow from the ER lumen into the cytoplasm, thereby producing
a transient elevation of cytosolic calcium that in turn activates
signal transduction kinases. Although IP3R are most
prominently located on the ER membrane, there is evidence for
localization of the IP3R to the plasma membrane, enabling
the IP3R to mediate entry of extracellular calcium into the
cytoplasm16 (and references therein). In cells undergoing apoptosis in response to ACS, immunocytochemical studies
localized the IP3R (specifically subtype 3) to the plasma
membrane.16 Upregulation of IP3R in S49
lymphoma cells was associated with increased cytosolic calcium
concentration, suggesting that increased expression of IP3R
on the plasma membrane increased calcium entry.16 Significantly, repression of ACS-induced IP3R expression by
transfecting cells with an IP3R antisense plasmid not only
decreased the induction of IP3R, but also inhibited the
induction of apoptosis by ACS.16
| |
RELATIONSHIP OF P2X1 AND IP3R TO EARLIER
EVIDENCE LINKING CALCIUM WITH ACS-INDUCED APOPTOSIS |
The involvement of calcium in ACS-induced apoptosis was first suggested
by Kaiser and Edelman,25 who discovered that extracellular calcium is necessary for induction of apoptosis in thymocytes by ACS.
This observation, which has been confirmed by others,12,13 suggests that extracellular calcium uptake mediates ACS-induced apoptosis. The concept that calcium signals ACS-induced apoptosis is
further supported by evidence that the calmodulin inhibitor, calmidazolium, interferes with ACS-induced thymocyte
apoptosis.26,27 However, in contrast to the situation in
thymocytes, extracellular calcium is unnecessary for ACS-induced
apoptosis of peripheral lymph node lymphocytes and lymphoma
cells.28-33
These earlier findings are fully consistent with the patterns of
expression of the P2X1 receptor. P2X1
expression was detected in thymocytes, but not in peripheral (lymph
node) T lymphocytes.15 Furthermore, there is a strong
correlation between P2X1 expression and the susceptibility
of individual thymocyte subsets to ACS-induced apoptosis. In the thymus
gland, immature CD4+CD8+ thymocytes residing
within the cortex are programmed to undergo apoptosis in response
to ACS, whereas the more mature
CD4+CD8
or
CD4CD8+ thymocytes located in the medulla
and circulating T lymphocytes are less sensitive to ACS-induced
apoptosis.34-37 Significantly, P2X1 expression
was detected only in CD4+CD8+ thymocytes, but
not in peripheral (lymph node) T lymphocytes.15
The earlier findings suggesting a role of extracellular calcium in
mediating ACS-induced apoptosis of thymocytes are also consistent with
evidence that ACS treatment increases the expression of the Type 3 IP3R in cortical, but not medullary,
thymocytes.16 However, evidence that ACS induce the
expression of Type 3 IP3R on the plasma membrane of S49
cells, a T-cell lymphoma line,16 appears to be less
consistent with earlier evidence indicating the extracellular calcium
is not required for induction of apoptosis in lymphoma cells by
ACS.29-32 Moreover, it is possible that the localization of
the IP3R to plasma membrane was a consequence of apoptotic
bleb formation in ACS-treated lymphoma cells. The apoptotic blebs that
form at the cell surface during apoptosis are membranous structures
composed of ER membrane.38 Thus, further work will be
required to determine whether IP3R induced by ACS treatment
are located primarily on the plasma membrane, or are located on the ER
membrane and then relocated to the cell surface as apoptotic blebs
form.
Although there is considerable evidence that extracellular calcium is
not required for apoptosis induction by ACS in lymphoma cells, a role
for calcium in mediating ACS-induced apoptosis of lymphoma cells has
been supported by several findings. First, calmodulin gene expression
is increased in T-cell lymphoma cells after treatment with
ACS.27 Second, calmidazolium interferes with apoptosis in
ACS-treated lymphoma cells.27 Third, stable expression of a
cDNA encoding the high-affinity calcium-binding protein, calbindin,
inhibited ACS-induced apoptosis in lymphoma cells.39 Where,
then, might the calcium come from that mediates ACS-induced apoptosis
in these cells? We and others have detected a diminution of the ER
calcium pool in ACS-treated lymphoma cells.33,40 Thus, one
theory is that calcium release from the ER, perhaps via
IP3R located on the ER membrane, may be involved in
signaling apoptosis in ACS-treated lymphoma cells.
| |
HOW DOES CALCIUM SIGNAL APOPTOSIS? |
Although the novel findings of the past year have provided molecular
evidence of a role for calcium in ACS-induced apoptosis, the specific
role that calcium plays in death induction and the signal transduction
pathway initiated by cytosolic calcium elevation and how it leads to
apoptosis are unknown. In the case of T-cell receptor (TCR)-mediated
apoptosis, calcium in combination with calmodulin activates
calcineurin, a cytosolic protein phosphatase that dephosphorylates and
thereby activates the transcription factor NF-ATC, leading
to increased transcription of calcium-regulated, immediate-early genes,
including Nur77.41 Calcineurin function, and hence
TCR-mediated apoptosis, is inhibited by the potent immunosuppressants cyclosporin A and FK506.42 However, these agents do not
inhibit ACS-induced apoptosis.42 Furthermore, ACS- and
TCR-mediated apoptotic pathways are mutually antagonistic42
and calcineurin activation protects T cells from ACS-induced
apoptosis.43 Also, Nur77 is not significantly induced by
ACS.41 One possible lead is a recently identified
calcium-binding protein, ALG-2, that has been implicated as necessary
for ACS-induced apoptosis, but its precise role in the apoptotic
process has not been defined.44
Another concept deserving further consideration is that while calcium
mediates apoptosis of ACS-treated cells, it might not be necessary for
ACS-induced cell death. This concept is based on a recent report by
Iseki et al,45 who found that high concentrations of the
intracellular calcium chelator Quin-2/AM inhibited DNA fragmentation in
ACS-treated thymocytes, but did not inhibit cell death. In their hands,
calmodulin inhibitors blocked DNA fragmentation, but markedly enhanced
cytolysis. One interpretation of these findings is that calcium might
be required for DNA cleavage during apoptosis, but not for cell death.
Thus, calcium might be involved in endonuclease activation, as part of
the degradation phase of apoptosis, but might not be necessary for cell
death.
However, the role of calcium in endonuclease activation varies among
different types of lymphocytes. Whereas the endonuclease responsible
for apoptotic DNA fragmentation in ACS-treated thymocytes requires
calcium for maximal activity,5,13,31,46-49 DNA is cleaved
by a calcium-independent endonuclease in the CEM human lymphoblast cell
line.50 These observations correlate with the evidence that
extracellular calcium uptake is required for ACS-induced thymocyte
apoptosis, but not for ACS-induced apoptosis of lymphoma cell.12,13,25,28
Another potential role for calcium in ACS-induced apoptosis might be in
protease activation. The calcium-dependent neutral protease, calpain,
is activated in the course of apoptosis induction in ACS-treated
thymocytes, and a calpain inhibitor appears to inhibit ACS-induced
thymocyte cell death.51 Moreover, destruction of the
nuclear structural protein lamin, an event that appears to precede
endonucleolytic DNA cleavage during ACS-induced apoptosis, is inhibited
by a calpain inhibitor.52,53 Currently, there is little
mechanistic insight into how ACS-induced cytosolic calcium elevation
might lead to activation of interleukin-1
converting enzyme-like
proteases, which clearly play a prominent role in ACS-induced
apoptosis, as well as other forms of
apoptosis.54
| |
SUMMARY |
Since the initial observations by Kaiser and Edelman,25,28
interest in the role of calcium in ACS-induced apoptosis has wavered,
in part because of the fact that extracellular calcium is only
necessary for induction of apoptosis in thymocytes, but not in
peripheral lymphocytes or lymphoma cells. Now, as a result of molecular
evidence implicating two separate ligand-gated calcium channels in
ACS-induced apoptosis, interest in the role of calcium is sure to be
renewed. The major challenge lies in determining the signal
transduction pathway through which ACS-induced calcium fluxes mediate
apoptosis.
| |
NOTE ADDED IN PROOF |
Recent results (Jayaraman T, Marks AR: Mol Cell Biol
17:3005, 1997) indicate that T cells deficient in IP3RI are
resistant to ACS-induced apoptosis, providing additional evidence for a role of calcium in signaling ACS-induced apoptosis.
| |
FOOTNOTES |
Submitted July 21, 1997;
accepted September 22, 1997.
Address reprint requests to Clark W. Distelhorst, MD, Division of
Hematology/Oncology, Department of Medicine, Case Western Reserve
University, 10900 Euclid Ave, Cleveland, OH, 44106-4937.
| |
REFERENCES |
1.
Dougherty TF,
White A:
Effect of pituitary adrenotropic hormone on lymphoid tissue.
Proc Soc Exp Biol Med
53:132,
1943
2.
Heilman RR,
Kendall EC:
The influence of 11-dehydro-17-hydroxy-corticosterone (compound E) on the growth of a malignant tumor in the mouse.
Endocrinology
34:416,
1944[Abstract/Free Full Text]
3.
Pearson OH,
Eliel LP,
Rawson RW,
Dobriner K,
Rhoads CP:
ACTH- and cortisone-induced regression of lymphoid tumors in man: A preliminary report.
Cancer
2:943,
1949
4.
Pearson OH,
Eliel LP:
Use of pituitary adrenocorticotropic hormone (ACTH) and cortisone in lymphomas and leukemias.
JAMA
144:1349,
1950
5.
Wyllie AH:
Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation.
Nature
284:555,
1980[Medline]
[Order article via Infotrieve]
6.
Raff MC:
Social controls on cell survival and cell death.
Nature
356:397,
1992[Medline]
[Order article via Infotrieve]
7.
Thompson CB:
Apoptosis in the pathogenesis and treatment of disease.
Science
267:1456,
1995[Abstract/Free Full Text]
8.
Yang E,
Korsmeyer SJ:
Molecular thanatopsis: A discourse on the BCL2 family and cell death.
Blood
88:386,
1996[Free Full Text]
9.
Sibley CH,
Tompkins GM:
Isolation of lymphoma cell variants resistant to killing by glucocorticoids.
Cell
2:213,
1974[Medline]
[Order article via Infotrieve]
10.
Beato M:
Gene regulation by steroid hormones.
Cell
56:335,
1989[Medline]
[Order article via Infotrieve]
11.
Helmberg A,
Auphan N,
Caelles C,
Karin M:
Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor.
EMBO J
14:452,
1995[Medline]
[Order article via Infotrieve]
12.
Wyllie AH,
Morris RG,
Smith AL,
Dunlop D:
Chromatin cleavage in apoptosis: Association with condensed chromatin morphology and dependence on macromolecular synthesis.
J Pathol
142:67,
1984[Medline]
[Order article via Infotrieve]
13.
Cohen JJ,
Duke RC:
Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death.
J Immunol
132:38,
1984[Abstract]
14.
Dieken ES,
Miesfeld RL:
Transcriptional transactivation functions localized to the glucocorticoid receptor N terminus are necessary for steroid induction of lymphocyte apoptosis.
Mol Cell Biol
12:589,
1992[Abstract/Free Full Text]
15.
Chvatchko Y,
Valera S,
Aubry J-P,
Renno T,
Buell G,
Bonnefoy J-Y:
The involvement of an ATP-gated ion channel, P2X1, in thymocyte apoptosis.
Immunity
5:275,
1996[Medline]
[Order article via Infotrieve]
16.
Khan AA,
Soloski MJ,
Sharp AH,
Schilling G,
Sabatini DM,
Li S-H,
Ross CA,
Snyder SH:
Lymphocyte apoptosis: Mediation by increased type 3 inositol 1,4,5,-trisphosphate receptor.
Science
273:503,
1996[Abstract]
17.
Owens GP,
Hahn WE,
Cohen JJ:
Identification of mRNAs associated with programmed cell death in immature thymocytes.
Mol Cell Biol
11:4177,
1991[Abstract/Free Full Text]
18.
Brake AJ,
Wagenbach MJ,
Julius D:
New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor.
Nature
371:519,
1994[Medline]
[Order article via Infotrieve]
19.
Valera S,
Hussy N,
Evans RJ,
Adami N,
North RA,
Surprenant A,
Buell G:
A new class of ligand-gated ion channel defined by P2x receptor for extracellular ATP.
Nature
371:516,
1994[Medline]
[Order article via Infotrieve]
20.
Pizzo P,
Zanovello P,
Bronte V,
Di Virgilio F:
Extracellular ATP causes lysis of mouse thymocytes and activates a plasma membrane ion channel.
Biochem J
274:139,
1991
21.
Zheng LM,
Zychlinsky A,
Liu C-C,
Ojcius DM,
Young JD-E:
Extracellular ATP as a trigger for apoptosis or programmed cell death.
J Cell Biol
112:279,
1991[Abstract/Free Full Text]
22.
North RA:
Families of ion channels with two hydrophobic segments.
Curr Opin Cell Biol
8:474,
1996[Medline]
[Order article via Infotrieve]
23.
Berridge MJ:
Inositol trisphosphate and calcium signalling.
Nature
361:315,
1993[Medline]
[Order article via Infotrieve]
24.
Clapham DE:
Calcium signaling.
Cell
80:259,
1995[Medline]
[Order article via Infotrieve]
25.
Kaiser N,
Edelman IS:
Calcium dependence of glucocorticoid-induced lymphocytolysis.
Proc Natl Acad Sci USA
74:632,
1977
26.
McConkey DJ,
Nicotera P,
Hartzell P,
Bellomo G,
Wyllie AH,
Orrenius S:
Glucocorticoids activate a suicide process in thymocytes through an elevation of cytosolic Ca2+ concentration.
Arch Biochem Biophys
269:365,
1989[Medline]
[Order article via Infotrieve]
27.
Dowd DR,
MacDonald PN,
Komm BS,
Haussler MR,
Miesfeld R:
Evidence for early induction of calmodulin gene expression in lymphocytes undergoing glucocorticoid-mediated apoptosis.
J Biol Chem
266:18423,
1991[Abstract/Free Full Text]
28.
Kaiser N,
Edelman IS:
Further studies on the role of calcium in glucocorticoid-induced lymphocytolysis.
Endocrinology
103:936,
1978[Abstract/Free Full Text]
29.
Nicholson ML,
Young DA:
Effect of glucocorticoid hormones in vitro on the structural integrity of nuclei in corticosteroid-sensitive and -resistant lines of lymphosarcoma P1798.
Cancer Res
38:3673,
1978[Abstract/Free Full Text]
30.
Nicholson ML,
Young DA:
Independence of the lethal actions of glucocorticoids on lymphoid cells from possible hormone effects on calcium uptake.
J Supramol Struct
10:165,
1979[Medline]
[Order article via Infotrieve]
31.
Alnemri ES,
Litwack G:
Glucocorticoid-induced lymphocytolysis is not mediated by an induced endonuclease.
J Biol Chem
264:4104,
1989[Abstract/Free Full Text]
32.
Bansal N,
Houle AG,
Melnykovych G:
Dexamethasone-induced killing of neoplastic cells of lymphoid derivation: Lack of early calcium involvement.
J Cell Physiol
143:105,
1990[Medline]
[Order article via Infotrieve]
33. Bian X, Hughes FM, Huang Y, Cidlowski JA, Putney JW: Roles of
cytoplasmic Ca2+ and intracellular Ca2+ stores in induction and
suppression of apoptosis in S49 cells. Am J Physiol 272 (Cell Physiol
41):C1241, 1997
34.
Claman HS:
Corticosteroids and lymphoid cells.
N Engl J Med
287:388,
1971
35.
Ranelletti FO,
Piantelli M,
Iacobelli S,
Musiani P,
Longo P,
Lauriola L,
Marchetti P:
Glucocorticoid receptors and in vitro corticosensitivity of peanut-positive and peanut-negative human thymocyte subpopulations.
J Immunol
127:849,
1981[Abstract]
36.
Cederig R,
Dialynas DP,
Fitch FW,
MacDonald HR:
Precursors of T cell growth factor producing cells in the thymus.
J Exp Med
158:1654,
1983[Abstract/Free Full Text]
37.
Cohen JJ:
Programmed cell death in the immune system.
Adv Immunol
50:55,
1991[Medline]
[Order article via Infotrieve]
38.
Casciola-Rosen LA,
Anhalt G,
Rosen A:
Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.
J Exp Med
179:1317,
1994[Abstract/Free Full Text]
39.
Dowd DR,
MacDonald PN,
Komm BS,
Haussler MR,
Miesfeld RL:
Stable expression of the calbindin-D28K complementary DNA interferes with the apoptotic pathway in lymphocytes.
Mol Endocrinol
6:1843,
1992[Abstract/Free Full Text]
40.
Lam M,
Dubyak G,
Distelhorst CW:
Effect of glucocorticosteroid treatment on intracellular calcium homeostasis in mouse lymphoma cells.
Mol Endocrinol
7:686,
1993[Abstract/Free Full Text]
41.
Liu Z-G,
Smith SW,
McLaughlin KA,
Schwartz LM,
Osborne BA:
Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77.
Nature
367:281,
1994[Medline]
[Order article via Infotrieve]
42.
Zacharchuk CM,
Mercep M,
Chakraborti PK,
Simons SS,
Ashwell JD:
Programmed T lymphocyte death: Cell activation- and steroid-induced pathways are mutually antagonistic.
J Immunol
145:4037,
1990[Abstract]
43.
Zhao Y,
Tozawa Y,
Iseki R,
Mukai M,
Iwata M:
Calcineurin activation protects T cells from glucocorticoid-induced apoptosis.
J Immunol
154:6346,
1995[Abstract]
44.
Vito P,
Lacana E,
D'Adamio LD:
Interfering with apoptosis: Ca2+-binding protein ALG-2 and alzheimer's disease gene ALG-3.
Science
271:521,
1996[Abstract]
45.
Iseki R,
Kudo Y,
Iwata M:
Early mobilization of Ca2+ is not required for glucocorticoid-induced apoptosis in thymocytes.
J Immunol
151:5198,
1993[Abstract]
46.
Vedeckis WV,
Bradshaw HDJ:
DNA fragmentation in S49 lymphoma cells killed with glucocorticoids and other agents.
Mol Cell Endocrinol
30:215,
1983[Medline]
[Order article via Infotrieve]
47.
Jones DP,
McConkey DJ,
Nicotera P,
Orrenius S:
Calcium-activated DNA fragmentation in rat liver nuclei.
J Biol Chem
264:6398,
1989[Abstract/Free Full Text]
48.
Gaido ML,
Cidlowski JA:
Identification, purification, and characterization of a calcium-dependent endonuclease (NUC18) from apoptotic rat thymocytes.
J Biol Chem
266:18580,
1991[Abstract/Free Full Text]
49.
Ellis RE,
Yuan J,
Horvitz HR:
Mechanisms and functions of cell death.
Annu Rev Cell Biol
7:663,
1991
50.
Alnemri ES,
Litwack G:
Activation of internucleosomal DNA cleavage in human CEM lymphocytes by glucocorticoid and novobiocin.
J Biol Chem
265:17323,
1990[Abstract/Free Full Text]
51.
Squier MKT,
Miller ACK,
Malkinson AM,
Cohen JJ:
Calpain activation in apoptosis.
J Cell Physiol
159:229,
1994[Medline]
[Order article via Infotrieve]
52.
Neamati N,
Fernanadez A,
Wright S,
Kiefer J,
McConkey DJ:
Degradation of lamin B1 precedes oligonucleosomal DNA fragmentation in apoptotic thymocytes and isolated thymocyte nuclei.
J Immunol
154:3788,
1995[Abstract]
53.
McConkey DJ:
Calcium-dependent, interleukin 1-converting enzyme inhibitor-insensitive degradation of lamin B1 and DNA fragmentation in isolated thymocyte nuclei.
J Biol Chem
271:22398,
1996[Abstract/Free Full Text]
54.
Henkart PA:
ICE family proteases: Mediators of all apoptotic cell death?
Cell
4:195,
1996
Introduction
References
Introduction
