Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells

Ciechomska, Iwona A.; Pyrzyńska, Beata; Kaźmierczak, Piotr; Kamińska, Bożena

doi:10.1038/sj.onc.1207137

Cited by 79 publications

(47 citation statements)

References 76 publications

(74 reference statements)

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“…One of the possible mechanisms through which FasL expression is regulated is via the Akt pathway (39,59,60). Although Akt has been shown to play an important role in T cell proliferation and survival (41,43,44), its role in the gp120-induced apoptosis of T cells is not known.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 gp120-mediated Apoptosis of T Cells Is Regulated by the Membrane Tyrosine Phosphatase CD45

Anand

Ganju

2006

Journal of Biological Chemistry

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The molecular mechanism of the human immunodeficiency virus type 1 (HIV-1) gp120-induced apoptosis of bystander T cells is not well defined. Here, we demonstrate that CD45, a key component of the T cell receptor pathway, plays a crucial role in apoptosis induced by HIV-1 gp120. We observed that HIV-1 gp120-induced apoptosis was significantly reduced in a CD45-deficient cell line and that reconstitution of CD45 in these cells restored gp120-induced apoptosis. However, expression of a chimeric protein containing only the intracellular phosphatase domain was not able to restore the apoptotic function in the CD45-negative clone, indicating an important role for the extracellular domain of CD45 in this function. The role of CD45 in gp120-induced apoptosis was further confirmed in T cell lines and peripheral blood mononuclear cells using a selective CD45 inhibitor as well as CD45-specific small interfering RNA. We also observed that gp120 treatment induced CD45 association with the HIV coreceptor CXCR4. Further elucidation of downstream signaling events revealed that CD45 modulates HIV-1 gp120-induced apoptosis by regulating Fas ligand induction and activation of the phosphoinositide 3-kinase/Akt pathway. These results suggest a novel CD45-mediated mechanism for the HIV envelope-induced apoptosis of T cells. The depletion of CD4ϩ T lymphocytes is a central pathogenic feature of human immunodeficiency virus type 1 (HIV-1) 2 infection and is largely responsible for the profound immunodeficiency characteristic of the late stages of HIV disease (1). Multiple mechanisms have been shown to contribute to the HIV-1-associated loss of CD4 ϩ T cells in HIV-1-infected individuals, among which the HIV-1-induced apoptosis of bystander uninfected cells is considered to be the most important (2-5). Several virally encoded proteins, including the envelope protein gp120, Tat, and Vpr, have been implicated in this process (3,6,7). Cumulative data demonstrate a major role for the HIV envelope glycoprotein in the death of uninfected lymphocytes (8, 9). The presence of measurable amounts of circulating soluble gp120 in HIV-infected subjects and the accumulation of a high concentration of envelope glycoproteins in lymphoid tissues underscore the potential for the envelope to contribute to T cell dysfunction (10, 11). A number of studies have indicated that HIV-1 gp120-induced apoptosis could represent an exacerbation of activation-induced cell death (12, 13). In fact, circulating T lymphocytes in HIV-1-infected patients are characterized by a high degree of immune activation (14, 15). Although immune activation may modulate HIV-mediated apoptosis, the molecular mechanisms involving the cross-talk between the T cell receptor (TCR) pathway and HIV-1 gp120 and leading to T cell loss are still unclear. Because the proteintyrosine phosphatase CD45 plays an essential role in TCR signaling (16 -18), it seemed reasonable to speculate that it may play a key role in HIV envelope-mediated apoptosis. CD45 is a transmembrane protein-tyrosine phosphatas...

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Section: Discussionmentioning

confidence: 99%

HIV-1 gp120-mediated Apoptosis of T Cells Is Regulated by the Membrane Tyrosine Phosphatase CD45

Anand

Ganju

2006

Journal of Biological Chemistry

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“…Whole-cell protein extracts were prepared from microglial cells as described (33). Antibodies recognizing phosphorylated kinases and total kinases were from Cell Signaling.…”

Section: Methodsmentioning

confidence: 99%

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

341

328

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for highly malignant gliomas (World Health Organization grade III and IV) there is no successful treatment; patients have an average survival time of approximately 1 y after diagnosis. Glioma cells are highly invasive and infiltrate normal brain tissue, and as a result, surgical resection is always incomplete. Degradation of ECM by membrane-bound and secreted metalloproteases facilitates glioma invasion. In particular, the membrane-bound metalloproteases are pivotal for tumor invasion as they very efficiently digest extracellular matrix proteins and also activate secreted metalloproteases (1) like matrix metalloproteinase-2 (MMP-2, also known as gelatinase A), which is one of the major proteases involved in glioma invasion in mouse models (2) and probably also in humans (3). Hence, membrane-inserted metalloproteases like membrane type 1 matrix metalloproteinase (MT1-MMP) can enable gliomas to invade the brain parenchyma as single cells (4).Microglia are the intrinsic immune cells of the brain; they control the innate and the adaptive immune response in the CNS and are activated by inflammatory or other pathological stimuli (5). Activation of microglial toll-like receptors (TLRs) triggers the innate immune response and can initiate host-defense and tissue repair mechanisms, but also CNS inflammation, neurodegeneration, and trauma (5, 6). As microglial cells are attracted toward glioma in large numbers-glioma tissue consists of as much as 30% microglial cells-and because microglia density in gliomas positively correlates with malignancy, invasiveness, and grading of the tumors (7-9), we investigated if microglia may actively contribute to glioma expansion. Here, we show that soluble factors released from glioma stimulate microglial TLRs, resulting in microglial MT1-MMP expression via the TLR downstream signaling molecules MyD88 and p38 MAPK. In turn, MT1-MMP expression and activity in these immune cells promotes glioma cell invasion and tumor expansion. ResultsGlioma Associated Microglia Over-Express MT1-MMP. We analyzed the expression pattern of the matrix protease MT1-MMP in mouse and human gliomas and found the enzyme to be expressed predominantly in microglial cells closely associated with the tumors. Whereas tumor-free human brain samples showed virtually no MT1-MMP expression, we detected intense MT1-MMP labeling, especially in higher-grade gliomas. Importantly, in human samples, immunolabeling for the microglial marker Iba1 and for MT1-MMP largely overlapped [supporting information (SI) Fig. S1 A-D and Table S1]. Likewise, after injection of a human glioma cell line (U373 cells) into immunodeficient mice, we detected that microglia represent the predominant cell type contributing intratumoral MT1-MMP expression (see Fig. S1E).In our in vivo mouse model, the glioma cells were identified by stable expression of EGFP and microglial cells by immunolabeling for Iba1. In sections obtained from mice 2 weeks after intracerebral injection with isogenic glioma cells (GL261 cells), we found an increased density of mic...

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“…Forkhead proteins act as important downstream targets of Akt/PKB, and their phosphorylation by Akt/PKB can regulate cell survival by operating their target genes [10,11]. Besides, forkhead proteins may inhibit cell proliferation by down-regulating cyclin D and promote apoptosis by up-regulating Fas ligand [12,13].…”

Section: Introductionmentioning

confidence: 99%

Forkhead protein FKHR and its phosphorylated form p-FKHR in human prostate cancer

Erdamar

Dai

et al. 2007

Human Pathology

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SummaryIn vitro studies suggest that the proapoptotic function of forkhead protein FKHR is probably inactivated by means of phosphorylation through the protein kinase B pathway. However, the clinical significance of FKHR in prostate cancer remains unclear. Six hundred forty radical prostatectomies were used for building tissue microarrays. Slides were stained with antibodies against FKHR and phosphorylated FKHR (p-FKHR). Correlations with clinicopathologic parameters were analyzed by Spearman rank test. Cox regression test and Kaplan-Meier test were used to determine the probability of disease recurrence, which is defined as a serum prostate-specific antigen (PSA) level greater than 0.4 ng/mL after radical prostatectomy. Nuclear FKHR level was higher in normal prostate than in benign prostatic hyperplasia and prostate cancer (P = .0000). Nuclear expression of FKHR was correlated with preoperative PSA level (ρ = 0.108, P = .029), extracapsular extension (ρ = 0.137, P = .005), and seminal vesicle invasion (ρ = 0.101, P = .039). FKHR expression was not a significant indicator of biochemical failure by either univariate or multivariate analysis. Nuclear p-FKHR expression correlated with patients' age (ρ = 0.179, P = .0003), Gleason score (ρ = 0.130, P = .0083), extracapsular extension (ρ = 0.227, P = .0000), clinical stage (Union Internationale Contre le Cancer system) (ρ = 0.166, P = .0007), and lymph node status (ρ = 0.101, P = .0401). Cytoplasmic p-FKHR correlated with patients' age (ρ = 0.146, P = .0030) and clinical stage (ρ = 0.117, P = .0180). Cytoplasmic p-FKHR was a significant indicator of biochemical recurrence (P = .0164; hazard ratio, 1.114-2.929). Nuclear p-FKHR strongly correlated with phosphorylated protein kinase B (ρ = 0.368, P = .0000), androgen receptor (ρ = 0.385, P = .0000), and Skp-2 (ρ = 0.170, P = .0036). Our data suggest that the proapoptotic role of FKHR is probably regulated by several signaling pathways in prostate cancer.

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Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells

Cited by 79 publications

References 76 publications

HIV-1 gp120-mediated Apoptosis of T Cells Is Regulated by the Membrane Tyrosine Phosphatase CD45

HIV-1 gp120-mediated Apoptosis of T Cells Is Regulated by the Membrane Tyrosine Phosphatase CD45

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Forkhead protein FKHR and its phosphorylated form p-FKHR in human prostate cancer

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