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PubMed2006

Activating transcription factor 3 and early growth response 1 are the novel targets of LY294002 in a phosphatidylinositol 3-kinase-independent pathway.

LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, has been widely used to study the function of PI3K in cellular responses. Based on its inhibitory effect on PI3K, LY294002 has been shown to exert antitumorigenic effect in vivo and in vitro. Here, we report that LY294002 alters early growth response 1 (EGR-1) phosphorylation and subsequently enhances activating transcription factor 3 (ATF3) expression independently of PI3K inhibition. This pathway may be, in part, responsible for the antitumorigenic effect of LY294002 in human colorectal cancer cells. ATF3 expression was increased by LY294002, followed by the induction of apoptosis in several colorectal cancer cell lines. This is consistent with results showing that the down-regulation of the ATF3 gene by small interfering RNA suppressed LY294002-induced apoptosis in HCT-116 cells. On the other hand, ATF3 expression was not affected by another PI3K inhibitor, wortmannin, as well as phosphatase and tensin homologue or dominant-negative Akt overexpression. We also found that LY294002 increases ATF3 promoter activity and the transactivation is partly mediated by a GC-rich sequence located in the promoter. EGR-1 binds to the ATF3 promoter as assessed by gel shift assay. Furthermore, phosphorylated EGR-1 was highly increased in LY294002-treated cells, indicating that EGR-1 phosphorylation induced by LY294002 may facilitate ATF3 transactivation. Our data suggest that EGR-1 acts as a mediator in LY294002-induced ATF3 expression via a PI3K-independent pathway. ATF3 and EGR-1 may provide a novel explanation for the antitumorigenic properties of LY294002 in human colorectal cancer cells.

Activating Transcription Factor 3↗
PubMed1999

Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR.

Insulin increases glucose uptake through the translocation of GLUT-4 via a pathway mediated by phosphatidylinositol 3-kinase (PI3K). In contrast, myocardial glucose uptake during ischemia and hypoxia is stimulated by the translocation of GLUT-4 to the surface of cardiac myocytes through a PI3K-independent pathway that has not been characterized. AMP-activated protein kinase (AMPK) activity is also increased by myocardial ischemia, and we examined whether AMPK stimulates glucose uptake and GLUT-4 translocation. In isolated rat ventricular papillary muscles, 5-aminoimidazole-4-carboxyamide-1-beta-D-ribofuranoside (AICAR), an activator of AMPK, as well as cyanide-induced chemical hypoxia and insulin, increased 2-[(3)H]deoxyglucose uptake two- to threefold. Wortmannin, a PI3K inhibitor, did not affect either the AICAR- or the cyanide-stimulated increase in deoxyglucose uptake but eliminated the insulin-stimulated increase in deoxyglucose uptake. Immunofluorescence studies demonstrated translocation of GLUT-4 to the myocyte sarcolemma in response to stimulation with AICAR, cyanide, or insulin. Preincubation of papillary muscles with the kinase inhibitor iodotubercidin or adenine 9-beta-D-arabinofuranoside (araA), a precursor of araATP (a competitive inhibitor of AMPK), decreased AICAR- and cyanide-stimulated glucose uptake but did not affect basal or insulin-stimulated glucose uptake. In vivo infusion of AICAR caused myocardial AMPK activation and GLUT-4 translocation in the rat. We conclude that AMPK activation increases cardiac muscle glucose uptake through translocation of GLUT-4 via a pathway that is independent of PI3K. These findings suggest that AMPK activation may be important in ischemia-induced translocation of GLUT-4 in the heart.

AMP-Activated Protein Kinases↗
PubMed2000

v-Crk activates the phosphoinositide 3-kinase/AKT pathway in transformation.

v-Crk induces cellular tyrosine phosphorylation and transformation of chicken embryo fibroblasts (CEF). We studied the molecular mechanism of the v-Crk-induced transformation. Experiments with Src homology (SH)2 and SH3 domain mutants revealed that the induction of tyrosine phosphorylation of cellular proteins requires only the SH2 domain, but both the SH2 and SH3 domains are required for complete transformation. Analysis of three well defined signaling pathways, the mitogen-activated protein kinase (MAPK) pathway, the Jun N-terminal kinase (JNK) pathway, and the phosphoinositide 3-kinase (PI3K)/AKT pathway, demonstrated that only the PI3K/AKT pathway is constitutively activated in v-Crk-transformed CEF. Both the SH2 and SH3 domains are required for this activation of the PI3K/AKT pathway in CEF. We also found that the colony formation of CEF is strongly induced by a constitutively active PI3K mutant, and that a PI3K inhibitor, LY294002, suppresses the v-Crk-induced transformation. These results strongly suggest that constitutive activation of the PI3K/AKT pathway plays an essential role in v-Crk-induced transformation of CEF.

Animals↗
PubMed2003

Activation of the Rap GTPases in B lymphocytes modulates B cell antigen receptor-induced activation of Akt but has no effect on MAPK activation.

Signaling by the B cell antigen receptor (BCR) activates the Rap1 and Rap2 GTPases, putative antagonists of Ras-mediated signaling. Because Ras can activate the Raf-1/ERK pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, we asked whether Rap activation limits the ability of the BCR to signal via these pathways. To do this, we blocked the activation of endogenous Rap1 and Rap2 by expressing the Rap-specific GTPase-activating protein RapGAPII. Preventing Rap activation had no effect on BCR-induced activation of ERK. In contrast, BCR-induced phosphorylation of Akt on critical activating sites was increased 2- to 3-fold when Rap activation was blocked. Preventing Rap activation also increased the ability of the BCR to stimulate Akt-dependent phosphorylation of the FKHR transcription factor on negative regulatory sites and decreased the levels of p27Kip1, a pro-apoptotic factor whose transcription is enhanced by FKHR. Moreover, preventing Rap activation reduced BCR-induced cell death in the WEHI-231 B cell line. Thus activation of endogenous Rap by the BCR limits BCR-induced activation of the PI3K/Akt pathway, opposes the subsequent inhibition of the FKHR/p27Kip1 pro-apoptotic module, and enhances BCR-induced cell death. Consistent with the idea that Rap-GTP is a negative regulator of the PI3K/Akt pathway, expressing constitutively active Rap2 (Rap2V12) reduced BCR-induced phosphorylation of Akt and FKHR. Finally, our finding that Rap2V12 can bind PI3K and inhibit its activity in a manner that depends upon BCR engagement provides a potential mechanism by which Rap-GTP limits activation of the PI3K/Akt pathway, a central regulator of B cell growth and survival.

Animals↗
PubMed2004

TIMP-1 stimulates proliferation of human aortic smooth muscle cells and Ras effector pathways.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional protein, which is found in most tissues and body fluids. Here, we demonstrated that recombinant TIMP-1 but not the synthetic matrix metalloproteinase inhibitor, GM6001, stimulated proliferation of human aortic smooth muscle cells (AoSMC) in a dose-dependent manner. The mitogenic effect was associated with activation of Ras, increased phosphorylation of ERK, and stimulation of cyclin D1 expression. The phosphatidylinositol 3-kinase (PI3K) signaling pathway was also involved since the PI3K inhibitor, LY294002, abolished the TIMP-1-mediated growth stimulation. These data suggest that TIMP-1 activates Ras, which then turns on the ERK and PI3K signaling pathways to promote cell cycle progression of the AoSMC.

Animals↗
PubMed2006

Therapeutic targets: MTOR and related pathways.

The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

Antibiotics, Antineoplastic↗
PubMed2005

Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration.

The lipid products of phosphoinositide 3-kinase (PI3K) are involved in many cellular responses such as proliferation, migration, and survival. Disregulation of PI3K-activated pathways is implicated in different diseases including cancer and diabetes. Among the three classes of PI3Ks, class I is the best characterized, whereas class II has received increasing attention only recently and the precise role of these isoforms is unclear. Similarly, the role of phosphatidylinositol-3-phosphate (PtdIns-3-P) as an intracellular second messenger is only just beginning to be appreciated. Here, we show that lysophosphatidic acid (LPA) stimulates the production of PtdIns-3-P through activation of a class II PI3K (PI3K-C2beta). Both PtdIns-3-P and PI3K-C2beta are involved in LPA-mediated cell migration. This study is the first identification of PtdIns-3-P and PI3K-C2beta as downstream effectors in LPA signaling and demonstration of an intracellular role for a class II PI3K. Defining this novel PI3K-C2beta-PtdIns-3-P signaling pathway may help clarify the process of cell migration and may shed new light on PI3K-mediated intracellular events.

Animals↗
PubMed2001

Neuregulin rescues PC12-ErbB4 cells from cell death induced by H(2)O(2). Regulation of reactive oxygen species levels by phosphatidylinositol 3-kinase.

Neuregulins (NRGs), a large family of transmembrane polypeptide growth factors, mediate various cellular responses depending on the cell type and receptor expression. We previously showed that NRG mediates survival of PC12-ErbB4 cells from apoptosis induced by serum deprivation or tumor necrosis factor-alpha treatment. In the present study we show that NRG induces a significant protective effect from H(2)O(2)-induced death. This effect of NRG is mediated by the phosphatidylinositol 3-kinase (PI3K)-signaling pathway since NRG failed to rescue cells from H(2)O(2) insult in the presence of the PI3K inhibitor, LY294002. Furthermore, the downstream effector of PI3K, protein kinase B/AKT, is activated by NRG in the presence of H(2)O(2), and protein kinase B/AKT activation is inhibited by LY294002. In addition, our results demonstrate that reactive oxygen species (ROS) elevation induced by H(2)O(2) is inhibited by NRG. LY294002, which blocks NRG-mediated rescue, increases ROS levels. Moreover, both H(2)O(2)-induced ROS elevation and cell death are reduced by expression of activated PI3K. These results suggest that PI3K-dependent pathways may regulate toxic levels of ROS generated by oxidative stress.

Animals↗
PubMed1999

Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt.

Extracellular signals often result in simultaneous activation of both the Raf-MEK-ERK and PI3K-Akt pathways (where ERK is extracellular-regulated kinase, MEK is mitogen-activated protein kinase or ERK kinase, and PI3K is phosphatidylinositol 3-kinase). However, these two signaling pathways were shown to exert opposing effects on muscle cell hypertrophy. Furthermore, the PI3K-Akt pathway was shown to inhibit the Raf-MEK-ERK pathway; this cross-regulation depended on the differentiation state of the cell: Akt activation inhibited the Raf-MEK-ERK pathway in differentiated myotubes, but not in their myoblast precursors. The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex.

Animals↗
PubMed2004

Cross-talk between protein kinases Czeta and B in cyclic AMP-mediated sodium taurocholate co-transporting polypeptide translocation in hepatocytes.

Cyclic AMP stimulates taurocholate (TC) uptake and sodium taurocholate co-transporting polypeptide (Ntcp) translocation in hepatocytes via the phosphoinositide-3 kinase (PI3K) signaling pathway. The aim of the present study was to determine whether protein kinase (PK) Czeta, one of the downstream mediators of the PI3K signaling pathway, is involved in cAMP-mediated stimulation of TC uptake. Studies were conducted in isolated rat hepatocytes and in HuH-7 cells stably transfected with rat liver Ntcp (HuH-Ntcp cells). Studies in hepatocytes showed that cAMP activates PKCzeta in a PI3K-dependent manner without inducing translocation of PKCzeta to the plasma membrane. Inhibition of cAMP-induced PKCzeta activity by myristoylated PKC (zeta/lambda) pseudosubstrate, a specific inhibitor of PKCzeta, and Gö 6850, a PKC inhibitor, resulted in inhibition of cAMP-induced increases in TC uptake and Ntcp translocation. Studies in HuH-Ntcp cells showed that inhibition of cAMP-induced PKCzeta activation by dominant-negative (DN) PKCzeta resulted in inhibition of cAMP-induced increases in TC uptake and Ntcp translocation. DN PKCzeta also inhibited wild-type PKCzeta-induced increases in PKCzeta activity, TC uptake, and Ntcp translocation. Myristoylated PKC (zeta/lambda) pseudosubstrate and DN PKCzeta also inhibited cAMP-induced activation of PKB in hepatocytes and HuH-Ntcp cells, respectively. Neither DN PKB nor constitutively active PKB affected cAMP-induced activation of PKCzeta, and wild-type PKCzeta did not activate PKB. Taken together, these results suggest that cAMP-induced activation of PKB is dependent on cAMP-induced stimulation of PKCzeta. It is proposed that cAMP-induced Ntcp translocation involves the activation of the PI3K/PKCzeta signaling pathway followed by the activation of the PI3K/PKB signaling pathway.

ATP-Binding Cassette Transporters↗
PubMed2004

The effects of clozapine on the GSK-3-mediated signaling pathway.

We investigated the effect of 10 microM clozapine on the activity of glycogen synthase kinase-3beta (GSK-3beta) and its upstream and downstream molecules in SH-SY5Y human neuroblastoma cells. Clozapine activates both Akt- and Dvl-mediated phosphorylation of GSK-3beta through phosphorylation at Ser9, and increased total cellular and intranuclear levels of beta-catenin. Pretreatment with the specific inhibitor of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, LY294002 (20 microM), prevented the phosphorylation of Akt but did not affect the phosphorylation of GSK-3beta. These results suggest that clozapine regulates the phosphorylation of GSK-3beta through Wnt signal pathways involving Dvl upstream but not through the PI3K-Akt pathway in SH-SY5Y cells.

Apoptosis↗
PubMed2004

Ras, PI3-kinase and mTOR signaling in cardiac hypertrophy.

Cardiac hypertrophy involves increased mass (growth) of the heart and a cardinal feature of this condition is increased rates of protein synthesis. Several signaling pathways have been implicated in cardiac hypertrophy including the phosphatidylinositol 3-kinase (PI3K) and Ras/Raf/MEK/Erk pathways. PI3K lies upstream of the mammalian target of rapamycin (mTOR), an important positive regulator of protein synthesis and cell growth. However, recent data suggest that, in response to certain hypertrophic agents, signaling via Ras and MEK/Erk, as well as mTOR, is required for activation of protein synthesis, indicating new connections between these key signaling pathways.

Animals↗
PubMed2006

A role for Akt in the rapid regulation of inflammatory and apoptotic pathways in mouse bladder.

Akt is linked to both inflammatory and neoplastic pathways. Akt activation is dependent on the phosphatidylinositol-3 kinase (PI3K) signaling pathways. Upon phosphorylation by PI3K, Akt can phosphorylate nuclear factor kappa B (NF-kappaB) and members of the forkhead family of transcription factors, which includes AFX. Our goal is to examine the effect of Escherichia coli lipopolysaccharide (LPS) on early cellular signaling in inflammatory (NF-kappaB) and apoptotic pathways (AFX) in a mouse-bladder model and in T-24 urothelial cancer cells. Female C57BL/6 mice were given an intraperitoneal (IP) injection of LPS or LPS free water and sacrificed 0-120 minutes later. Bladders were harvested, and immunohistochemistry (IHC) and/or immunoblotting performed using antibodies to PI3K, inhibitor kappa B-alpha (IkappaB-alpha), and total and phosphorylated Akt, NF-kappaB and AFX. Levels of IkappaB-alpha and total and phosphorylated Akt and NF-kappaB were determined in T-24 cells treated with LPS for 0-120 minutes. Bladders and T-24 cells were treated with PI3K inhibitors in some experiments. Protein amounts in different samples were normalized to immunoreactive actin. Phosphorylated and non-phosphorylated species of Akt, NF-kappaB, and AFX were localized to the urothelium. IP LPS injection rapidly (within 30 minutes) increased Akt phosphorylation. IP LPS injection decreased IkappaB-alpha levels, and increased NF-kappaB and AFX phosphorylation. Wortmannin effectively blocked phosphorylation of Akt in LPS-treated mice, and also reduced phosphorylation of AFX and, to a lesser extent, NF-kappaB. After treatment with LPS, Akt and NF-kappaB phosphorylation was rapidly increased in T-24 cells. Akt phosphorylation, and to a lesser extent NF-kappaB phosphorylation, were blocked by LY-294,002. LPS/PI3K/Akt is a cellular signaling pathway which rapidly activates downstream pathways of inflammation and neoplasia in bladder urothelium.

Animals↗
PubMed2004

IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1.

Muscle atrophy results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin ligases (E3s): atrogin-1 and muscle ring finger 1 (MuRF1). Glucocorticoids are essential for many types of muscle atrophy, and their effects are opposite to those of insulin-like growth factor I (IGF-I) and insulin, which promote growth. In myotubes, dexamethasone (Dex) inhibited growth and enhanced breakdown of long-lived cell proteins, especially myofibrillar proteins (as measured by 3-methylhistidine release), while also increasing atrogin-1 and MuRF1 mRNA. Conversely, IGF-I suppressed protein degradation and prevented the Dex-induced increase in proteolysis. IGF-I rapidly reduced atrogin-1 expression within 1 h by blocking mRNA synthesis without affecting mRNA degradation, whereas IGF-I decreased MuRF1 mRNA slowly. IGF-I and insulin also blocked Dex induction of these E3s and several other atrophy-related genes ("atrogenes"). Changes in overall proteolysis with Dex and IGF-I correlated tightly with changes in atrogin-1 mRNA content, but not with changes in MuRF1 mRNA. IGF-I activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and inhibition of this pathway [but not the calcineurin-nuclear factor of activated T cell (NFAT) or the MEK-ERK pathway] increased proteolysis and atrogin-1 mRNA expression. Thus an important component of growth stimulation by IGF-I, through the PI3K-Akt pathway, is its ability to rapidly suppress transcription of the atrophy-related E3 atrogin-1 and other atrogenes and degradation of myofibrillar proteins.

Blotting, Northern↗
PubMed2002

Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor.

Cannabinoids, the active components of marijuana and their endogenous counterparts, exert many of their actions in brain through the seven-transmembrane receptor CB(1). This receptor is coupled to the activation of the extracellular signal-regulated kinase (ERK) cascade. However, the precise molecular mechanism for CB(1)-mediated ERK activation is still unknown. Here, we show that in U373 MG human astrocytoma cells, CB(1) receptor activation with the cannabinoid agonist delta(8)-tetrahydrocannabinol dimethyl heptyl (HU-210) was coupled to ERK activation and protection from ceramide-induced apoptosis. HU-210-induced ERK activation was inhibited by tyrphostin AG1478 and PP2, widely employed inhibitors of the epidermal growth factor receptor (EGF(R)) and the Src family of cytosolic tyrosine kinases, respectively. However, HU-210 stimulation resulted in neither EGF(R) phosphorylation, Src tyrosine phosphorylation, nor increased Src activity. In addition, dominant-negative forms of both proteins were unable to prevent cannabinoid-induced ERK activation, thus excluding the existence of CB(1)-mediated EGF(R) transactivation or Src activation. Wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294,002), inhibitors of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, blocked cannabinoid-induced ERK activation. Likewise, HU-210 stimulated the PI3K downstream targets protein kinase B (PKB), as shown by its phosphorylation in Thr 308 and Ser 473 residues, and Raf-1. Moreover, betagamma subunit release mimicked ERK and PI3K/PKB activation, suggesting that activation of class IB PI3K mediates cannabinoid action. Pro-survival HU-210 action also required activation of both PI3K and ERK signaling pathways. In conclusion, CB(1)-induced ERK activation was mediated by PI3K(IB) and this effect may have important consequences in the control of cell death/survival decision.

Apoptosis↗
PubMed2006

Glial-derived neurotrophic factor (GDNF) prevents ethanol (EtOH) induced B92 glial cell death by both PI3K/AKT and MEK/ERK signaling pathways.

We investigated the neuroprotective effect of glial-derived neurotrophic factor (GDNF) upon alcohol-exposed B92 cultures, as well as the role of the cytoskeleton and mitogen-activated protein kinase (MAPK) pathways in this effect. Ethanol (EtOH) was added to cultures, either alone or in combination with 30 ng/ml GDNF. Exposure to EtOH (86 and 172 mM; 60 and 120 min) increased the frequency of apoptotic cells identified by nuclear DNA staining with 4,6-diamidino-2-phenylindole (DAPI). Cultures treated with GDNF showed a decrease in ethanol-induced apoptosis. A jun N-terminal kinase (JNK) pathway is activated by EtOH and their pharmacological inhibition (by SP600125) neutralized ethanol-induced apoptosis, suggesting a role for JNK in EtOH neurotoxicity. Immunocytochemically detected phospho-JNK (p-JNK) showed an unusual filamental expression, and localized together with actin stress fibers. Examination of the cytoskeleton showed that EtOH depolymerized actin filaments, inducing p-JNK dissociation and translocation to the nucleus, which suggests that released p-JNK may contribute to glial cell death after EtOH exposure. Treatment with GDNF, in turn, may neutralize the ethanol-induced cell death pathway. Either a phosphatidylinositol 3-kinase (PI3K)/AKT pathway inhibitor (LY294002) or an inhibitor of the extracellular signal-regulated kinase (ERK) 1, 2 pathways (UO126) failed to neutralize GDNF protective effects. However, the simultaneous use of both inhibitors blocked the protective effect of GDNF, suggesting a role for both signaling cascades in the GDNF protection. These findings provide further insight into the mechanism involved in ethanol-induced apoptosis and the neurotrophic protection of glial cells.

Actin Cytoskeleton↗
PubMed2006

Regulation of TopBP1 oligomerization by Akt/PKB for cell survival.

Regulation of E2F1-mediated apoptosis is essential for proper cellular growth. This control requires TopBP1, a BRCT (BRCA1 carboxyl-terminal) domain-containing protein, which interacts with E2F1 but not other E2Fs and represses its proapoptotic activity. We now show that the regulation of E2F1 by TopBP1 involves the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, and is independent of pocket proteins. Akt phosphorylates TopBP1 in vitro and in vivo. Phosphorylation by Akt induces oligomerization of TopBP1 through its seventh and eighth BRCT domains. The Akt-dependent oligomerization is crucial for TopBP1 to interact with and repress E2F1. Akt phosphorylation is also required for interaction between TopBP1 and Miz1 or HPV16 E2, and repression of Miz1 transcriptional activity, suggesting a general role for TopBP1 oligomerization in the control of transcription factors. Together, this study defines a novel pathway involving PI3K-Akt-TopBP1 for specific control of E2F1 apoptosis, in parallel with cyclin-Cdk-Rb for general control of E2F activities.

Animals↗
PubMed2006

Brain genomics of intracerebral hemorrhage.

After intracerebral hemorrhage (ICH), many changes of gene transcription occur that may be important because they will contribute to understanding mechanisms of injury and recovery. Therefore, gene expression was assessed using Affymetrix microarrays in the striatum and the overlying cortex at 24 h after intracranial infusions of blood into the striatum of adult rats. Intracerebral hemorrhage regulated 369 of 8,740 transcripts as compared with saline-injected controls, with 104 regulated genes shared by the striatum and cortex. There were 108 upregulated and 126 downregulated genes in striatum, and 170 upregulated and 69 downregulated genes in the cortex. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed upregulation of IL-1-beta, Lipcortin 1 (annexin) and metallothionein 1,2, and downregulation of potassium voltage-gated channel, shaker-related subfamily, beta member 2 (Kcnab2). Of the functional groups of genes modulated by ICH, many metabolism and signal-transduction-related genes decreased in striatum but increased in adjacent cortex. In contrast, most enzyme, cytokine, chemokine, and immune response genes were upregulated in both striatum and in the cortex after ICH, likely in response to foreign proteins from the blood. A number of these genes may contribute to brain edema and cellular apoptosis caused by ICH. In addition, downregulation of growth factor pathways and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway could also contribute to perihematoma cell death/apoptosis. Intracerebral hemorrhage-related downregulation of GABA-related genes and potassium channels might contribute to perihematoma cellular excitability and increased risk of post-ICH seizures. These genomic responses to ICH potentially provide new therapeutic targets for treatment.

Animals↗