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PubMed1976

Endgoenous protein kinase in outer plasma membrane of cultured 3T3 cells. Nature of the membrane-bound substrate and effect of cell density, serum addition, and oncogenic transformation.

Endogenous protein kinase activity was detected in the outer plasma membrane of 373 and SV40 transformed 3T3 cells. When intact cells were incubated with [gamma-32P]ATP, there was a transfer of [32P]phosphate into an acid-insoluble product. The reaction was: (a) linear as a function of time (up to 30 min), (b) proportional to the number of cells present and (c) dependent on temperature and Mg2+ concentration. The acid-insoluble product was susceptible to pronase but not RNase or DNase. More specifically, phosphomonoester bonds to serine and threonine were identified. There was less than 3% hydrolysis of the [gamma-32P]ATP during the reaction; moreover, free [32P]phosphate failed to substitute for the ATP. The reaction product was located on the cell surface, as evidenced by the fact that it could be removed by mild trypsin treatment of intact 3T3 cells. Further evidence for the surface location of the kinase was shown by its activity in phosphorlating exogenous substrate, histone, and phosvitin. The level of phosphorylation increased by 2- to 4-fold prior to the start of S phase when quiescent 3T3 cells were stimulated to reinitiate growth by the addition of serum. The SV40 3T3 cells had from 5- to 10-fold more activity per cell than the quiescent 3T3 cells. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and radioautography show at least 25 phosphorylated proteins; the surface label pattern of 3T3 cells differs from that of SV40-transformed 3T3 cells.

Cell Count↗

PubMed1990

Identification and partial purification of a chromatin bound calmodulin activated histone 3 kinase from calf thymus.

A calcium-calmodulin (Ca2(+)-CaM) stimulated histone H3 phosphorylating activity was identified as a component of a nuclear protein complex purified from a 150 mM NaCl extract of calf thymus chromatin. This activity bound to a CaM-Sepharose affinity column in a Ca2+ dependent manner and was eluted off the column in the presence of EGTA. Equilibrium centrifugation of the EGTA eluate on a sucrose density gradient revealed that the activity is a component of a larger complex identified at 25% sucrose. This complex consisted of two major proteins, having Mr of 65 and 75 kDa. Using [125I] CaM and the gel overlay technique it was shown that the 75 kDa protein is the major CaM binding protein in the complex.

Animals↗

PubMed2005

A histone code in meiosis: the histone kinase, NHK-1, is required for proper chromosomal architecture in Drosophila oocytes.

To promote faithful propagation of the genetic material during sexual reproduction, meiotic chromosomes undergo specialized morphological changes that ensure accurate segregation of homologous chromosomes. The molecular mechanisms that establish the meiotic chromosomal structures are largely unknown. We describe a mutation in a recently identified Histone H2A kinase, nhk-1, in Drosophila that leads to female sterility due to defects in the formation of the meiotic chromosomal structures. The metaphase I arrest and the karyosome, a critical prophase I chromosomal structure, require nucleosomal histone kinase-1 (NHK-1) function. The defects are a result of failure to disassemble the synaptonemal complex and to load condensin onto the mutant chromosomes. Embryos laid by nhk-1-/- mutant females arrest with aberrant polar bodies and mitotic spindles, revealing that mitosis is affected as well. We analyzed the role of Histone H2A phosphorylation with respect to the histone code hypothesis and found that it is required for acetylation of Histone H3 and Histone H4 in meiosis. These studies reveal a critical role for histone modifications in chromosome dynamics in meiosis and mitosis.

Animals↗

PubMed1978

Autophosphorylation of rabbit skeletal muscle cyclic AMP-dependent protein kinase I catalytic subunit.

The catalytic subunit of rabbit skeletal muscle cyclic AMP-dependent protein kinase I can catalyze self-phosphorylation. The autophosphorylation reaction uses ATP as the phosphoryl donor, requires Mg2+, and is inhibited by polyarginine. Prior treatment of the catalytic subunit with Escherichia coli alkaline phosphatase in the presence of bovine serum albumin greatly enhances the autophosphorylation of the subunit. The protein-bound phosphate is stable in acid but labile in base. Incubation of the 32P-labeled phosphoenzyme with histones led neither to the phosphorylation of histones nor to a loss of radioactivity from the phosphoenzyme. The results suggest that the phosphoenzyme does not represent an intermediate of the phosphotransferase reaction.

Animals↗

PubMed2005

Haspin: a mitotic histone kinase required for metaphase chromosome alignment.

The fidelity of chromosome segregation during cell division is critical to maintain genomic stability and to prevent cancer and birth defects. A key set of kinases that regulates this process has been identified and characterized over the last few years, including the Aurora, Polo and Nek families. Recently we proposed that a little-studied kinase known as haspin is a new member of this important group. During mitosis haspin is phosphorylated, associates with the chromosomes, centrosomes and spindle, and is responsible for phosphorylation of histone H3 at threonine-3. Depletion of haspin using RNA interference prevents normal alignment of chromosomes at metaphase, suggesting that haspin plays a crucial role in chromosome segregation. Here we discuss possible mechanisms of haspin action and the function of histone phosphorylation in mitosis. We also outline some of the questions raised by these new findings and consider what role haspin might play in cancer.

Amino Acid Sequence↗

PubMed1992

Partial displacement of histone H1 from chromatin is required before it can be phosphorylated by mitotic H1 kinase in vitro.

The massive nonselective and reversible phosphorylation of histone H1 during mitosis is a universal phenomenon among eukaryotes. The growth-associated kinase responsible for this phosphorylation is identical to the maturation promoting factor, a key regulator of the cell cycle. Here we showed that growth-associated kinase, isolated from mitotic HeLa cells which were capable of phosphorylating HeLa H1 in vitro with high activity and mostly at the same sites phosphorylated during mitosis in vivo (assayed by two-dimensional analysis of tryptic phosphopeptides), did not significantly phosphorylate chromatin-bound or nuclear H1 in vitro. Its inability to phosphorylate chromatin-bound H1 did not change when the amount of kinase was increased or the incubation was prolonged. The resistance of chromatin-bound H1 to phosphorylation did not result from chromatin aggregation. Rapid phosphorylation of H1 in vitro, as well as in a nuclear system, was restored when NaCl concentrations were raised above 200 mM where H1:DNA interactions are weakened. At 300 mM NaCl, chromatin-bound H1 was phosphorylated in a subset of the sites observed for free H1 phosphorylated in vitro. These results suggest that active displacement of H1 from chromatin DNA may take place before H1 can be fully phosphorylated during mitosis.

Autoradiography↗

PubMed1998

Angiotensin II potentiates DNA synthesis in AT-1 transformed cardiomyocytes.

Angiotensin II has been shown to be mitogenic in various cell types. In cultured neonatal cardiomyocytes, we have demonstrated that angiotensin II causes hypertrophy, not hyperplasia. However, fetal or neonatal cardiomyocytes exhibit limited proliferation in primary culture, and are mitotically less potent. In order to determine whether angiotensin II is simply a hypertrophic or hyperplastic growth factor for mitotically-potent cardiomyocytes, we analysed [3H]-thymidine uptake and cell cycle-regulated gene expression using SV40 large T-transformed AT-1 cardiomyocytes. Angiotensin II, alone and in combination with other growth factors, increased [3H]-thymidine uptake in a dose-dependent manner. The mRNA expression of G1 cyclins (Cyclin C, D1, D2, D3) and histone H1-kinase activity by CDK2 increased 6 h after angiotensin II stimulation. Western blot analysis revealed cyclin B1 expression after 18 h , which peaked at 30 h. Histone H1-kinase activity by cdc2 was also increased by angiotensin II, and peaked at 24-36 h, indicating that these changes were cell cycle dependent. Double immunofluorescent photography showed that AT-1 cells incorporated BrdU, and expressed cdc2 by angiotensin II stimulation. [3H]-thymidine and BrdU uptake were blocked by losartan, but not by PD123319. In contrast with neonatal cardiomyocytes, angiotensin II potentiated DNA synthesis and induced cell cycle regulated gene expression in AT-1 cardiomyocytes, and this activity was mediated by the angiotensin II type-1 receptor.

Angiotensin II↗

PubMed1983

Regulation of cAMP-dependent protein kinase subunit levels in Friend erythroleukemic cells. Effects of differentiation and treatment with 8-Br-cAMP and methylisobutyl xanthine.

Friend erythroleukemic cells contain both type I and type II cAMP-dependent protein kinases. The amounts of type I and type II regulatory subunits (R I and R II) were established by a combination of the equilibrium binding of cyclic [3H]AMP and specific immunoprecipitation. In control cells the total specific cAMP-binding activity was 9.8 pmol/mg of cytosolic protein and the ratio of R II to R I was 1.2. After the induction of differentiation by growth in 2% dimethyl sulfoxide, the total cAMP-binding capacity doubled, but larger and opposing changes in R II and R I levels were observed. The concentration of R II tripled (to 16.6 pmol/mg) while R I content (1.5 pmol/mg) declined to one-third of the control cell level, resulting in an R II:R I value of 11.1. Treatment of Friend cells with 0.5 mM 8-bromoadenosine 3':5'-monophosphate (8-Br-cAMP) and 0.2 mM methylisobutyl xanthine for 2 days did not stimulate cell differentiation. however, the cAMP-binding capacity nearly doubled and the cells accumulated a high level of R II while R I declined. This resulted in a distribution of R subunits closely resembling that of differentiated cells. Cyclic AMP-stimulated histone kinase activity increased in proportion to cAMP-binding activity during differentiation; no such increase was seen following 8-Br-cAMP treatment. Fractionation of cytosolic extracts by DEAE-cellulose chromatography revealed that both R I and R II were fully associated with the catalytic subunit (C) of protein kinase before and after differentiation. In extracts of 8-Br-cAMP-treated cells all of R I and 40 to 60% of R II were not associated with C. Free R II isolated from these cells was indistinguishable from RII present in holoenzyme. Thus, erythroid differentiation of Friend cells results in a coordinate accumulation of R II and C subunits as well as a decline in R I content. In contrast, chronic exposure to 8-Br-cAMP elicits similar changes in R subunit levels but disrupts the coordinate regulation of R and C content.

1-Methyl-3-isobutylxanthine↗

PubMedDate not supplied

[Study by the spin-label method of relaxation properties of protein kinase, its subunits and the catalytic subunit--histone H1 complex].

Using the spin label method, the rotational relaxation in solution of adenosine 3',5'-monophosphate-dependent protein kinase and its subunits as well as the complexes of the enzyme with the substrate, histone H1, was studied. The rotational correlation time of the spin labeled macromolecules was measured on the basis of the quantitative estimation of the label mobility in relation to the protein globule. The holoenzyme molecule was found to be a rigid sphere. Whereas the complex of the globular catalytic subunit of the enzyme with a specific protein substrate, the spin labeled histone H1, appeared a flexible formation. The relaxation properties of the histone H1 molecule selectively labeled by the spin label in its globular part were investigated.

Animals↗

PubMed1979

A cyclic GMP-dependent histone kinase bound to liver nucleoli.

A method of steady-state electrophoresis in polyacrylamide gels was used to analyze the presence of cyclic nucleotide binding components in cell extracts. Multiple cyclic AMP and cyclic GMP binding components were detected in soluble cytoplasmic and nuclear extracts derived from avian liver, but only a single cyclic GMP binding protein was found in the 0.3 M NaCl extract of liver nucleoli. In the presence of cyclic GMP, this protein phosphorylated efficiently a calf thymus histone mixture and an endogenous nucleolar protein, which migrated identically with histone H4 in sodium dodecyl sulfate polyacrylamide gel electrophoresis. The isoelectric point of the cyclic GMP-binding protein was 4.8. Addition of cyclic GMP did not influence the activity of the endogenous nucleolar RNA polymerase.

Animals↗

PubMed1995

Differential effect of activators of protein kinase C on cytoskeletal changes in mouse and hamster eggs.

Treatment of metaphase II-arrested hamster eggs with activators of protein kinase C has been reported to promote resumption of the cell cycle, second polar body emission, and pronucleus formation (G.I. Gallicano, S.M. Schwarz, R.W. McGaughey, and D.G. Capco, 1993, Dev. Biol. 156, 94-106). In contrast, we have not observed these responses in mouse eggs obtained from CF-1 mice treated with these activators. In this report, we evaluated if this difference was due to differences in the technique used for PKC stimulation in the two different laboratories or due to species differences. Metaphase II-arrested hamster or mouse eggs were treated with phorbol diesters for 5 min or with a membrane-permeable diacylglycerol for 1 hr. Treatment of hamster eggs resulted in (1) the formation of "second polar body-like structures" commencing 5 min after treatment and reaching a maximum by 20-40 min; (2) a remarkable increase in the staining of filamentous actin in the region of these polar body-like structures; and (3) the disassembly of spindle microtubules. A reduction in cdc2/cyclin B1 kinase activity, as assessed by a decrease in H1 kinase activity, as well as progression from metaphase to anaphase were not observed. Treatment of mouse eggs from either CF-1 or CD-1 mice with these activators of PKC did not result in the formation of these polar body-like structures, did not cause an increase in filamentous actin, and did not result in a reduction in histone H1 kinase activity. This treatment, however, did induce disassembly of the spindle microtubules and the formation of multiple "pronucleus-like structures" that were more discernible in eggs from CD-1 mice. We conclude that the "apparent" activation of hamster eggs by activators of PKC is due to the effect of these agents on the cytoskeleton, which gives rise to structures that appear similar to polar bodies, but without any evidence of cell cycle resumption. The different responses seen in mouse and hamster eggs are mainly due to differences in the sensitivity of the cytoskeleton to rearrangements induced by these agents.

Amino Acid Sequence↗

PubMed2002

The ability to develop an activity that transfers histones onto sperm chromatin is acquired with meiotic competence during oocyte growth.

Following fertilization, the oocyte remodels the sperm chromatin into the male pronucleus. As a component of this process, during meiotic maturation, oocytes develop an activity that transfers histones onto sperm DNA. To further characterize this activity, we tested whether oocytes at different stages of growth could, upon entry into metaphase of maturation, transfer histones onto sperm DNA, as judged by chromatin morphology and immunocytochemistry. Meiotically competent growing oocytes, which spontaneously enter metaphase upon culture, transferred histones onto sperm chromatin, whereas incompetent oocytes did not, even when treated with okadaic acid to induce germinal vesicle breakdown (GVBD) and chromosome condensation. When incompetent oocytes were cultured until they acquired the ability to undergo GVBD, only a small proportion also developed histone-transfer activity during maturation. However, this proportion significantly increased when the oocytes were cultured as granulosa-oocyte complexes. The failure of histone-transfer activity to develop in incompetent oocytes treated with okadaic acid was not linked to low H1 kinase activity nor rescued by injected histones. Because competent, but not incompetent, oocytes produce natural calcium oscillations, incompetent oocytes were exposed to SrCl2. One-third of treated oocytes produced at least one Ca2+ oscillation and, following insemination, the same proportion transferred histones onto sperm DNA. Histone transfer did not occur in oocytes pretreated with the Ca2+ chelator, BAPTA-AM. These results indicate that the ability to develop histone-transfer activity is acquired by growing oocytes near the time of meiotic competence, that it is separable from this event, and that it may be regulated through a Ca2+-dependent process.

Animals↗

PubMed1999

Oncogenic potential of cyclin E in T-cell lymphomagenesis in transgenic mice: evidence for cooperation between cyclin E and Ras but not Myc.

To study the oncogenic activity of cyclin E in an in vivo system we generated transgenic mice expressing high levels of cyclin E in T-lymphocytes by using a construct containing the CD2 locus control region. These animals were neither predisposed to develop any tumors spontaneously nor showed an increased incidence when crossbred with Emu L-myc transgenic mice but developed hyperplasia in peripheral lymphoid organs at later age with an incidence of 27%. When treated with the DNA methylating carcinogen N-methylnitrosourea (MNU) that provokes the development of T-cell lymphomas, CD2-cyclin E transgenic animals came down with T-cell neoplasia showing a significant higher incidence (54%) than normal non transgenic controls (31%). In one of eight tumors that arose in normal MNU treated mice we could find an expected activating point mutation in the Ki-ras gene (12.5%). In contrast, the same mutation occurred in five of 16 tumors from CD2-cyclin E transgenic mice (31.2%). Whereas cyclin E overexpression alone did not lead to an increased CDK2 activity we observed in all tumors that emerged from either MNU treated normal mice or treated CD2-cyclin E transgenics a downregulation of p27KIP1 and a higher histone H1 kinase activity in CDK2 immunoprecipitates compared to normal tissue. These findings demonstrate that high level expression of cyclin E can predispose T-cells for hyperplasia and malignant transformation. However, the results also suggest that this activity of cyclin E is manifest only when other cooperating oncogenes in particular ras genes are present and activated. This would be consistent with our previous finding that cyclin E and Ha-Ras cooperate in focus formation assays in rat embryo fibroblasts.

Animals↗

PubMed1991

Proteolysis of nuclear proteins by mu-calpain and m-calpain.

Purified calpains are capable of proteolyzing several high Mr nuclear proteins and solubilizing a histone H1 kinase activity from rat liver nuclei upon exposure to 10(-6) - 10(-5) M Ca2+. Major nuclear substrates displayed apparent molecular masses of 200, 130, 120, and 60 kDa on Coomassie Blue-stained SDS-PAGE gels. The nuclear proteins and the H1 kinase were released from Triton-treated nuclei following incubation with buffer containing 0.5 M NaCl. They therefore appeared to be internal nuclear matrix proteins. The nuclear H1 kinase activity solubilized by incubation with m-calpain was eluted in the void volume of a Bio-Gel A-1.5m column, indicating an apparent mass greater than 1,500 kDa. Treatment of the calpain-solubilized kinase with 0.5 M NaCl dissociated it to a form having an apparent mass of 300 kDa (Stokes radius = 5.6 nm), suggesting that the 300-kDa (Stokes radius = 5.6 nm), nuclei by calpain treatment as a large complex containing other internal matrix proteins. Purified human erythrocyte mu-calpain was capable of proteolyzing the nuclear matrix proteins at 10(-6) M Ca2+. In contrast, human erythrocyte multicatalytic protease complex produced little cleavage of the nuclear proteins. Proteolysis of nuclear proteins by either mu-calpain or m-calpain was inhibited by calpastatin. These experiments suggest a physiologic role for the calpains in the turnover of nuclear proteins.

Animals↗

PubMed1987

Protein kinase activity associated with Fc gamma 2a receptor of a murine macrophage like cell line, P388D1.

The properties of protein kinase activity associated with Fc receptor specific for IgG2a (Fc gamma 2aR) of a murine macrophage like cell line, P388D1, were investigated. IgG2a-binding protein isolated from the detergent lysate of P388D1 cells by affinity chromatography on IgG-Sepharose was found to contain four distinct proteins of Mr 50,000, 43,000, 37,000, and 17,000, which could be autophosphorylated upon incubation with [gamma-32P]ATP. The autophosphorylation of Fc gamma 2a receptor complex ceased when exogenous phosphate acceptors (casein or histone) were added in the reaction mixture. Casein was found to be a much better phosphate acceptor than histone in this system, as casein incorporated about 32-fold more 32P than histone did. Phosphorylation of casein catalyzed by Fc gamma 2a receptor complex was dependent on casein concentration (maximum phosphate incorporation being at 0.5 mg/mL), increased with time or temperature, was dependent on the concentration of ATP and Mg2+, and was maximum at pH near 8. Casein phosphorylation was significantly inhibited by a high concentration of Mn2+ (greater than 25 mM) or KCl (greater than 100 mM) or by a small amount of heparin (greater than 10 units/mL) and was enhanced about 2-fold by protamine. Casein kinase activity associated with Fc gamma 2a receptor used ATP as substrate with an apparent Km of 2 microM as well as GTP with an apparent Km of 10 microM. Prior heating (60 degrees C for 15 min) or treatment with protease (trypsin or Pronase) of Fc gamma 2a receptor complex almost totally abolished casein kinase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Influence of recipient oocyte cell cycle stage on DNA synthesis, nuclear envelope breakdown, chromosome constitution, and development in nuclear transplant bovine embryos.

Nuclear transplantations into metaphase II (MII) and S phase oocyte cytoplasm were performed to investigate the influence of recipient cell cycle stage on nuclear function and development of bovine nuclear transplant (NT) embryos. Rate of inactivation of histone H1 kinase and duration of DNA synthesis in activated oocytes were determined. The proportion of S phase blastomeres in in vivo produced day 5.5 bovine embryos was measured. DNA synthesis was also assessed in NT embryos after transfer into MII and S phase cytoplasm. MII NT embryos were produced by fusing a blastomere into a MII oocyte; the fusion pulse served to activate the oocyte. S NT embryos were produced by fusing a blastomere into an early S phase oocyte electrically activated 4 h prior to fusion. Nuclear envelope structure, chromosome constitution, and extent of development were examined in MII and S NT embryos. Histone H1 kinase activity dropped to baseline within 2 h of electrical activation. A second electrical pulse did not alter H1 kinase activity when delivered 4 h after the first pulse. The frequency of S phase blastomeres in day 5.5 bovine embryos ranged from 79% to 100%, depending on the duration of culture in 3H-thymidine. Nuclear transplantation into MII cytoplasm resulted in a transient drop in DNA synthesis over 3.5 h. DNA synthesis resumed at 4.5 h post activation (hpa), concomittantly with initiation of DNA replication in activated oocytes. In contrast, DNA synthesis was not interrupted after transfer into S phase cytoplasm. DNA synthesis persisted until 13.5 hpa, as in activated oocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

cdc2 is a component of the M phase-specific histone H1 kinase: evidence for identity with MPF.

A so-called "growth-associated" or "M phase-specific" histone H1 kinase (H1K) has been described in a wide variety of eukaryotic cell types. In starfish oocytes, the hormone 1-methyladenine triggers synchronous meiotic divisions that are accompanied by a rapid 30-fold stimulation of H1K activity. We have substantially purified this activated enzyme and find that it is enriched for a protein of 34 kd. Quantitative immunoblotting of the column fractions with antibodies raised against p34, the product of the fission yeast cdc2 gene, revealed complete coelution of the H1K activity and a 34 kd anti-cdc2 cross-reactive protein. Starfish H1K also displayed the same apparent molecular weight, on a molecular sizing column, as the mitotically activated p13/p34/p62 protein kinase complex of HeLa cells. p13, the product of the fission yeast suc1+ gene, interacts tightly with p34 in yeast, Xenopus, and HeLa cells. H1K from starfish binds strongly to p13-Sepharose and the time course of 1-methyladenine-induced H1K activation, whether assayed in crude extract or on p13-Sepharose beads, is identical. These results indicate that a cdc2 homolog is a subunit of the M phase-specific H1K of starfish meiotic oocytes. Since this protein is also a subunit of the M-phase promoting factor (MPF) of Xenopus oocytes, we suggest that H1K and MPF are the same entity, and that histone H1 is likely to be one substrate of the pleiotropic MPF.

Adenine↗

PubMed2002

Down regulation of p53 with HPV E6 delays and modifies cell death in oxidant response of human diploid fibroblasts: an apoptosis-like cell death associated with mitosis.

The tumor suppressor p53 protein is known to play a critical role in apoptosis. In normal human diploid fibroblasts (HDFs), expression of the human papillomaviral (HPV) E6 gene results in a reduction of p53 protein and an inhibition of oxidant induced apoptosis within 24 h. In comparison, expression of the HPV E7 gene causes down-regulation of Rb protein without inhibiting apoptosis. Here we determine whether HDFs expressing E6 undergo cell death with a delayed time course following H2O2 exposure. Appearances of caspase-3 activity, cell detachment, trypan blue uptake and aberrant nuclei were all delayed in E6 cells compared to wild type (wt) or E7 cells. A mutant E6 gene that failed to reduce p53 could not delay cell death. Morphological examination revealed nuclear condensation in dying wt or E7 cells but nuclear fragmentation in E6 cells. Flow cytometry analysis indicated an S phase distribution of dying wt or E7 cells but a G2/M phase distribution of dying E6 cells. An elevation of cyclin B was observed in dying E6 cells but not in apoptotic E7 cells. Dying E6 cells also had elevated levels of cdc-2 protein and histone kinase activity, suggesting that the cells died at mitosis. Electron microscopy studies showed that E6 cells may die at prophase or prometaphase. Overexpression of bcl-2 resulted in an inhibition of both caspase-3 and death of E7 or E6 cells. Inactivating caspases with zVAD-fmk also reduced the death rate of E7 and E6 cells. Our data indicate that expression of HPV E6 causes a delay and morphological modification of cell death induced by oxidants. E6 cells die at mitosis, which can be inhibited by bcl-2 overexpression or caspase inhibition.

Annexin A5↗