The role of proto-oncogenes in coronary restenosis

doi:10.1016/S0033-0620(97)80004-7

Progress in Cardiovascular Diseases

Volume 40, Issue 2, September–October 1997, Pages 117-128

https://doi.org/10.1016/S0033-0620(97)80004-7 Get rights and content

Arterial injury results in exposure of medial smooth muscle cells and adventitial fibroblasts to multiple growth factors that bind to specific cell surface receptors. These in turn activate second messengers and induce expression of immediate-early genes within minutes to hours after ligand binding to the receptor. Activation of the immediate-early genes results in passage of the stimulated cell from its nonproliferating, quiescent G₀ state to the first phase of the cell cycle (G₁). Coordination of the events that occur during the cell cycle is effected by a series of cyclin-dependent kinases and requires inactivation of several “tumor suppressor genes,” including p53, p21, p16, p15, p27, and the retinoblastoma gene Rb, that inhibit the kinase activity of the cyclin/Cdk complexes. An understanding of the factors that regulate signal transduction, cell cycle progression, and programmed cell death has suggested several novel therapeutic strategies including (1) antisense oligonucleotide inhibition of proto-oncogene expression, (2) the use of molecular decoys or pharmacological therapies to block specific steps required for cell cycle progression, and (3) gene transfer of tumor suppressor genes. The apparent success of several of these strategies in animal models of restenosis suggests that these molecular therapies may play a valuable role in preventing intimal hyperplasia and restenosis after balloon angioplasty and vascular stenting.

References (101)

EllisSG et al.
Arterial injury and the enigma of coronary restenosis
J Am Coll Cardiol
(1992)
Di MarioC et al.
Quantitative assessment with intracoronary ultrasound of the mechanisms of restenosis after percutaneous transluminal coronary angioplasty and directional coronary atherectomy
Am J Cardiol
(1995)
SavageM et al.
Long-term angiographic and clinical outcome after implantation of a balloon-expandable stent in the native coronary circulation
J Am Coll Cardiol
(1994)
UllrichA et al.
Signal transduction by receptors with tyrosine kinase activity
Cell
(1990)
CantleyLC et al.
Oncogenes and signal transduction
Cell
(1991)
VogelsteinB et al.
p53 function and dysfunction
Cell
(1992)
SymondsH et al.
p53-dependent apoptosis suppresses tumor growth and progression in vivo
Cell
(1994)
ChenPL et al.
Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation
Cell
(1989)
WeirL et al.
Expression of gax, a growth arrest homeobox gene, is rapidly down-regulated in the rat carotid artery during the proliferative response to balloon injury
J Biol Chem
(1995)
RanjanV et al.
Fluid shear stress induces synthesis and nuclear localization of c-fos in cultured human endothelial cells
Biochem Biophys Res Commun
(1993)

The Bypass Angioplasty Revascularization (BARI) Investigators

Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease

N Engl J Med

(1996)

GruntzigAR et al.

Nonoperative dilation of coronary artery stenosis. Percutaneous transluminal coronary angioplasty

N Engl J Med

(1979)

LiuM et al.

Restenosis after coronary angioplasty: Potential biologic determinants and role of intimal hyperplasia

Circulation

(1989)

ClowesAW et al.

Mechanisms of stenosis after arterial injury

Lab Invest

(1983)

LafontA et al.

Restenosis after experimental angioplasty. Intimal, medial, and adventitial changes associated with constrictive remodeling

Circ Res

(1995)

PostMJ et al.

The relative importance of arterial remodeling compared with intimal hyperplasia in lumen renarrowing after balloon angioplasty. A study in the normal rabbit and the hypercholesterolemic yucatan micropig

Circulation

(1994)

AndersenH et al.

Remodeling rather than neointimal formation explains luminal narrowing after deep vessel wall injury. Insights from a porcine coronary (re)stenosis model

Circulation

(1996)

MintzGS et al.

Arterial remodeling after coronary angioplasty. A serial intravascular ultrasound study

Circulation

(1996)

TopolEJ et al.

Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease

Circulation

(1995)

SerruysP et al.

A comparison of balloon expandable stent implantation with balloon angioplasty in patients with coronary artery disease

N Engl J Med

(1994)

ScottNA et al.

Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries

Circulation

(1996)

ClowesAW et al.

Kinetics of cellular proliferation after arterial injury. I. Smooth muscle cell growth in the absence of endothelium

Lab Invest

(1983)

O'BrienE et al.

Proliferation in primary and restenotic coronary atherectomy tissue: Implications for antiproliferative therapy

Circulation Research

(1993)

PickeringJ et al.

Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization

J Clin Invest

(1993)

WilliamsL

Signal transduction by the platelet-derived growth factor receptor

Science

(1989)

PardeeA

G1 events and regulation of cell proliferation

Science

(1989)

BravoR

Genes induced during the G0/G1 transition in mouse fibroblasts

Semin Cancer Biol

(1990)

MianoJ et al.

Early proto-oncogene expression in rat aortic smooth muscle cells following endothelial removal

Am J Pathol

(1990)

BautersC et al.

Proto-oncogene expression in rabbit aorta after wall injury. First marker of the cellular process leading to restenosis after angioplasty?

Eur Heart J

(1992)

MarmurJD et al.

Induction of PDGF-responsive genes in vascular smooth muscle: Implications for the early response to vessel injury

Circulation

(1992)

TaubmanM et al.

JE mRNA accumulates rapidly in aortic injury and in platelet-derived growth factor-stimulated vascular smooth muscle cells

Circ Res

(1992)

TravaliS et al.

Effect of the myb gene product on the expression of the PCNA gene in fibroblasts

Oncogene

(1991)

FreemanR et al.

Protein kinases and protooncogenes: Biochemical regulators of the eukaryotic cell cycle

Biochemistry

(1991)

HartwellL et al.

Cell cycle control and cancer

Science

(1994)

AlexandrowM et al.

Transforming growth factor β and cell cycle regulation

Cancer Res

(1995)

MarxJ

New tumor suppressor may rival p53

Science

(1994)

AntoniadesH et al.

p53 expression during normal tissue regeneration in response to acute cutaneous injury in swine

J Clin Invest

(1994)

LiR et al.

Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair

Nature

(1994)

SerraR et al.

Tumor suppressor genes in the TGF-β signaling pathway?

Nature Medicine

(1996)

DeCaprioJA et al.

The retinoblastoma-susceptibility gene product becomes phosphorylated in multiple stages during cell cycle entry and progression

StellerH

Mechanisms and genes of cellular suicide

Science

(1995)

BennettM et al.

The molecular basis of apoptosis

Heart Failure

(1994)

Yonish-RouachE et al.

Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6

Nature

(1991)

LoweSW et al.

p53 is required for radiation-induced apoptosis in mouse thymocytes

Nature

(1993)

XiaZ et al.

Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis

Science

(1995)

BennettM et al.

Apoptosis of human vascular smooth muscle cells derived from normal and coronary atherosclerotic plaques

J Clin Invest

(1995)

IsnerJ et al.

Apoptosis in human atherosclerosis and restenosis

Circulation

(1995)

HanDK et al.

Evidence for apoptosis in human atherogenesis and in rat vascular injury model

Am J Pathol

(1995)

Bochaton-PiallatM et al.

Apoptosis participates in cellularity regulation during rat aortic intimal thickening

Am J Pathol

(1995)

GengY et al.

Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta

Arterioscler Thromb Vasc Biol

(1996)

Cited by (47)

MicroRNA-451 inhibits vascular smooth muscle cell migration and intimal hyperplasia after vascular injury via Ywhaz/p38 MAPK pathway
2019, Experimental Cell Research
Increasing evidence has indicated that intimal hyperplasia is a common event in the pathophysiology of many vascular diseases including atherosclerosis (AS). Recently, deregulated microRNAs (miRNAs) have been reported to be associated with the pathophysiology of AS. However, the biological function and regulatory mechanisms of miRNAs in intimal hyperplasia in AS remain largely unclear. The aim of this study was to investigate the effects of miRNAs on intimal hyperplasia and reveal the underlying mechanisms of their effects. Firstly, the model of rat vascular injury was successfully constructed in vivo. Then, the miRNAs expression profiles were analyzed by miRNA microarray. It was observed that miR-451 was significantly downregulated in injury carotid arteries. Subsequently, we investigated miR-451 function and found that upregulation of miR-451 by agomir-451 improves intimal thickening in rats following vascular injury. It was also observed that miR-451 was downregulated in the VSMCs following platelet-derived growth factor type BB (PDGF-BB) stimulation. The upregulation of miR-451 attenuated PDGF-BB-induced VSMCs injury, as evidenced by inhibition of proliferation, invasion and migration. Besides, overexpression of miR-451 blocked the activation of p38 MAPK signaling pathway in PDGF-BB treated VSMCs, as demonstrated by the downregulation of phosphorylated (p-) p38. In addition, Ywhaz, a positive regulator of p38 MAPK signaling pathway, was found to be a direct target of miR-451 in the VSMCs and this was validated using a luciferase reporter assay. Overexpression of Ywhaz partially abolished the inhibitory effects of miR-451 overexpression on PDGF-BB induced VSMCs injury. Collectively, these findings indicated that miR-451 protected intimal hyperplasia and PDGF-BB-induced VSMCs injury by Ywhaz/p38 MAPK pathway, and miR-451 may be considered as a potential therapeutic target in the treatment of AS.
EPO gene expression promotes proliferation, migration and invasion via the p38MAPK/AP-1/MMP-9 pathway by p21WAF1 expression in vascular smooth muscle cells
2015, Cellular Signalling
The use of recombinant human erythropoietin (rHuEpo) can lead to hypertrophy and hyperplasia, and has induced the proliferation of vascular smooth muscle cells (VSMCs). The effect of the EPO gene in the migration and invasion of VSMCs remains unclear. In this study, overexpression of the EPO gene increased the DNA synthesis and phosphorylation of ERK1/2 and p38MAPK in VSMCs. In addition, EPO gene expression induced the migration and invasion of VSMCs via the expression of MMP-9 by the activation of NF-κB and AP-1 binding. A blockade of p38MAPK by specific p38MAPK inhibitor SB203580 led to a suppression of the increased DNA synthesis, migration, and invasion of VSMCs that was induced by the EPO gene. SB203580 treatment blocked the increased expression of MMP-9 through the binding activity of AP-1. Transfection of the EPO gene with VSMCs was associated with the up-regulation of cyclin D1/CDK4, cyclin E/CDK2, and p21WAF1, and with the down-regulation of p27KIP1. The specific suppression of p21WAF1 expression by siRNA rescued the enhancement of DNA synthesis via the phosphorylation of p38MAPK and the increase in migration and invasion through AP-1-mediated MMP-9 expression in EPO gene transfectants. These novel findings demonstrate that p21WAF1 regulates the proliferation, migration and invasion of VSMC induced by EPO gene.
Inhibitory effect of a novel naphthoquinone derivative on proliferation of vascular smooth muscle cells through suppression of platelet-derived growth factor receptor β tyrosine kinase
2014, European Journal of Pharmacology
Citation Excerpt :
The binding of PDGF to the PDGF-Rβ leads to its phosphorylation at multiple tyrosine residues. The activated PDGF-Rβ is associated with a number of SH2 domain-containing proteins, including the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) and phospholipase C (PLC) γ1 (Muller, 1997). Several molecules have been implicated in mitogen-activated protein kinase (MAPK) signaling pathways, such as extracellular regulated kinases 1 and 2 (ERK1/2) by triggering activation of Raf-1.
This study was designed to investigate the antiproliferative effect of a novel naphthoquinone derivative, 2‐undecylsulfonyl‐5,8‐dimethoxy‐1,4‐naphthoquinone (2-undecylsulfonyl-DMNQ), on platelet-derived growth factor (PDGF)-stimulated vascular smooth muscle cells (VSMCs) and examine the possible molecular mechanism of its antiproliferative action. 2-Undecylsulfonyl-DMNQ significantly inhibited PDGF-stimulated cell number and DNA synthesis, and arrested the PDGF-stimulated progression through G₀/G₁ to S phase of cell cycle supported by the suppression of pRb phosphorylation and cyclin D1/E, CDK2/4 and PCNA expressions. 2-Undecylsulfonyl-DMNQ dose-dependently inhibited the PDGF-stimulated phosphorylation of phospholipase Cγ (PLCγ), protein kinase B (Akt/PKB), signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK 1/2). In addition, 2-undecylsulfonyl-DMNQ inhibited PDGF-induced PDGF receptor β (PDGF-Rβ) dimerization and the phosphorylation of Tyr^579/581, Tyr⁷¹⁶, Tyr⁷⁵¹ and Tyr¹⁰²¹ in PDGF-Rβ. However, 2-undecylsulfonyl-DMNQ has no antiproliferative effect on epidermal growth factor (EGF)- or fetal bovine serum (FBS)-stimulated VSMCs. In conclusion, these findings suggest that the antiproliferative effects of 2-undecylsulfonyl-DMNQ on PDGF-stimulated VSMCs are due to the blockade of receptor dimerization and autophosphorylation on specific tyrosine residues of PDGF-Rβ, which resulted in the subsequent suppression of signaling cascades and a cell cycle arrest. Our observation may explain an important mechanism to block the integration of multiple signals generated by growth factor receptor activation for prevention of VSMC proliferation in cardiovascular diseases.
Tangeretin, a citrus flavonoid, inhibits PGDF-BB-induced proliferation and migration of aortic smooth muscle cells by blocking AKT activation
2011, European Journal of Pharmacology
Citation Excerpt :
AKT, MAPKs and PLCγ are the downstream components of the PDGF signaling pathway (Fredriksson et al., 2004; Heldin et al., 1998). A number of receptor tyrosine kinases, including the receptors for PDGF-BB, activate PI3K/AKT, MAPKs and PLCγ, and their signaling pathways are important in early intracellular signal transduction for cell growth, migration and survival (Muller, 1997). Among the MAPK family, ERK1/2 has been implicated in the growth of various cell types including VSMCs (Wei et al., 1997).
Tangeretin, a natural polymethoxylated flavone concentrated in the peel of citrus fruits, is known to have antiproliferative, antiinvasive, antimetastatic and antioxidant activities. However, the effect of tangeretin on vascular smooth muscle cells (VSMCs) is unknown. This study examined the effect of tangeretin on platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of rat aortic smooth muscle cells (RASMCs) as well as its underlying mechanisms. Tangeretin significantly inhibited proliferation, DNA synthesis and migration of PDGF-BB-stimulated RASMCs without inducing cell death. Treatment with tangeretin-induced cell-cycle arrest in the G₀/G₁ phase was associated with down-regulation of cyclin D1 and cyclin E in addition to up-regulation of p27^kip1. We also showed that tangeretin inhibited PDGF-BB-induced phosphorylation of AKT, while it had no effect on the phosphorylation of phospholipase Cγ (PLCγ), PDGF receptor β-chain (PDGF-Rβ) and extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs). An in vitro kinase assay revealed that tangeretin inhibited AKT activity in a dose-dependent manner. Moreover, treatment of LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, had similar effects than that of tangeretin on the expression of p27^kip1 and cyclin D1, as well as cell migration in PDFG-BB-stimulated RASMCs. Taken together, these findings suggest that tangeretin could suppress PDGF-BB-induced proliferation and migration of RASMCs through the suppression of PI3K/AKT signaling pathway, and may be a potential candidate for preventing or treating vascular diseases, such as atherosclerosis and restenosis.
Combined superoxide dismutase mimetic and peroxynitrite scavenger protects against neointima formation after endarterectomy in association with decreased proliferation and nitro-oxidative stress
2010, European Journal of Vascular and Endovascular Surgery
Citation Excerpt :
Furthermore, we observed a rapid up-regulation of the proto-oncogenes c-Jun and c-Fos in the carotid arteries 1 h after endarterectomy. As described by several authors, activation of proto-oncogenes contributes to the very early phase of neointima formation; then, their level drops to baseline in the following stages of restenosis development.28,29 Indeed, we found c-Jun and c-Fos expression in control CEA group to be identical to those of the sham group.
Reactive oxygen and nitrogen species (e.g., peroxynitrite) may trigger neointima formation leading to restenosis. In a rat carotid endarterectomy (CEA) model, we investigated the effects of the manganese(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP), a superoxide dismutase (SOD) mimetic and peroxynitrite scavenger on neointima formation.
CEA was performed in male Sprague–Dawley rats. Animals received either vehicle (control group; n = 15) or 15 mg kg⁻¹ day⁻¹ MnTBAP intraperitoneally for 3 weeks (treatment group; n = 13). Four groups of carotids were analysed: the left, uninjured carotids (sham) and the right, injured carotids (control CEA) from the control group, the right, injured carotids from the treatment group (CEA + MnTBAP) and an additional group of carotids that were harvested 1 h following endarterectomy. The analysis of carotid arteries was performed by histology, immunohistochemistry and real-time polymerase chain reaction (PCR). Plasma malondialdehyde (MDA) levels were measured by lipid hydroperoxidase assay.
Stenosis rate (10.5 ± 8.1% vs. 45.4 ± 28.3%), the percentage of proliferating cell nuclear antigen-positive cells (13.4 ± 7.1% vs. 23.3 ± 11.0%) and nitrotyrosine immunoreactivity (5.8 ± 1.9 vs. 8.0 ± 2.0) were significantly reduced in the vascular wall of the CEA + MnTBAP group compared with control CEA group. Ratio of Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL)-positive nuclei was significantly lower after antioxidant therapy (41.7 ± 26.7% vs. 64.9 ± 18.5%). Plasma MDA levels increased after endarterectomy (11.7 ± 4.8 vs. 4.1 ± 2.0 μmol l⁻¹) and reduced in the treatment group (3.2 ± 2.1 μmol l⁻¹). No significant gene regulation after MnTBAP treatment could be noted.
MnTBAP decreased neointima formation, which was associated with reduced vascular smooth muscle cell proliferation and attenuated local and systemic nitro-oxidative stress.
Pterostilbene, a natural dimethylated analog of resveratrol, inhibits rat aortic vascular smooth muscle cell proliferation by blocking Akt-dependent pathway
2010, Vascular Pharmacology
Vascular smooth muscle cells (VSMCs) are the main cellular component in the arterial wall, and abnormal proliferation of VSMCs plays a central role in the pathogenesis of atherosclerosis and restenosis after angioplasty, and possibly in the development of hypertension. Pterostilbene, a natural dimethylated analog of resveratrol, is known to have diverse pharmacological activities including anti-cancer, anti-inflammation and anti-oxidant activities. The present study was designed to investigate the effects of pterostilbene on platelet-derived growth factor (PDGF)-BB-induced VSMCs proliferation as well as the molecular mechanisms of the antiproliferative effects. The cell growth of VSMCs was determined by cell counting and [³H]thymidine incorporation assays. Pterostilbene significantly inhibited the DNA synthesis and proliferation of PDGF-BB-stimulated VSMCs in a concentration-dependent manner. The inhibition percentages of pterostilbene at 1, 3 and 5 μM to VSMCs proliferation were 68.5, 80.7 and 94.6%, respectively. The DNA synthesis of pterostilbene at 1, 3 and 5 μM in VSMCs was inhibited by 47.4, 76.7 and 100%, respectively. Pterostilbene inhibited the PDGF-BB-stimulated phosphorylation of Akt kinase. However, pterostilbene did not change the expression of extracellular signal-related kinase (ERK) 1/2, PLCγ1, phosphatidylinositol (PI)3 kinase and PDGF-Rβ phosphorylation. In addition, pterostilbene down-regulated the cell cycle-related proteins including the expression of cyclin-dependent kinase (CDK) 2, cyclin E, CDK4, cyclin D1, retinoblastoma (Rb) proteins and proliferative cell nuclear antigen (PCNA). These findings suggest that the inhibition of pterostilbene to the cell proliferation and DNA synthesis of PDGF-BB-stimulated VSMCs may be mediated by the suppression of Akt kinase. Furthermore, pterostilbene may be a potential anti-proliferative agent for the treatment of atherosclerosis and angioplasty restenosis.

View all citing articles on Scopus

View full text

The role of proto-oncogenes in coronary restenosis

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

Cell

Cell

Cell

Cell

Cell

J Biol Chem

Biochem Biophys Res Commun

Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease

N Engl J Med

Nonoperative dilation of coronary artery stenosis. Percutaneous transluminal coronary angioplasty

N Engl J Med

Restenosis after coronary angioplasty: Potential biologic determinants and role of intimal hyperplasia

Circulation

Mechanisms of stenosis after arterial injury

Lab Invest

Restenosis after experimental angioplasty. Intimal, medial, and adventitial changes associated with constrictive remodeling

Circ Res

The relative importance of arterial remodeling compared with intimal hyperplasia in lumen renarrowing after balloon angioplasty. A study in the normal rabbit and the hypercholesterolemic yucatan micropig

Circulation

Remodeling rather than neointimal formation explains luminal narrowing after deep vessel wall injury. Insights from a porcine coronary (re)stenosis model

Circulation

Arterial remodeling after coronary angioplasty. A serial intravascular ultrasound study

Circulation

Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease

Circulation

A comparison of balloon expandable stent implantation with balloon angioplasty in patients with coronary artery disease

N Engl J Med

Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries

Circulation

Kinetics of cellular proliferation after arterial injury. I. Smooth muscle cell growth in the absence of endothelium

Lab Invest

Proliferation in primary and restenotic coronary atherectomy tissue: Implications for antiproliferative therapy

Circulation Research

Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization

J Clin Invest

Signal transduction by the platelet-derived growth factor receptor

Science

G1 events and regulation of cell proliferation

Science

Genes induced during the G0/G1 transition in mouse fibroblasts

Semin Cancer Biol

Early proto-oncogene expression in rat aortic smooth muscle cells following endothelial removal

Am J Pathol

Proto-oncogene expression in rabbit aorta after wall injury. First marker of the cellular process leading to restenosis after angioplasty?

Eur Heart J

Induction of PDGF-responsive genes in vascular smooth muscle: Implications for the early response to vessel injury

Circulation

JE mRNA accumulates rapidly in aortic injury and in platelet-derived growth factor-stimulated vascular smooth muscle cells

Circ Res

Effect of the myb gene product on the expression of the PCNA gene in fibroblasts

Oncogene

Protein kinases and protooncogenes: Biochemical regulators of the eukaryotic cell cycle

Biochemistry

Cell cycle control and cancer

Science

Transforming growth factor β and cell cycle regulation

Cancer Res

New tumor suppressor may rival p53

Science

p53 expression during normal tissue regeneration in response to acute cutaneous injury in swine

J Clin Invest

Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair

Nature

Tumor suppressor genes in the TGF-β signaling pathway?

Nature Medicine

The retinoblastoma-susceptibility gene product becomes phosphorylated in multiple stages during cell cycle entry and progression

Mechanisms and genes of cellular suicide

Science

The molecular basis of apoptosis

Heart Failure

Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6

Nature

p53 is required for radiation-induced apoptosis in mouse thymocytes

Nature

Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis

Science