Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV infection predisposes to cancer during childhood. In addition to the AIDS-defining non-Hodgkin lymphoma (NHL) and Kaposi sarcoma, a range of other lymphoid malignancies and solid tumors have been described. We report the first case of an HIV-positive child with thymic carcinoma in the setting of regressing thymic cysts. The tumor expressed CKIT but failed to respond to imatinab mesylate after a transient response to multiagent chemotherapy. This case extends the spectrum of pediatric malignancy in the setting of HIV and suggests that patients with presumed benign thymic cysts require ongoing surveillance.
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PMID:Thymic carcinoma in a child with HIV infection. 1631 59

Tat, the transactivator of HIV-1 gene expression, is released by acutely HIV-1-infected T-cells and promotes adhesion, migration, and growth of inflammatory cytokine-activated endothelial and Kaposi's sarcoma cells. It has been previously demonstrated that these effects of Tat are due to its ability to bind through its arginine-glycine-aspartic (RGD) region to the alpha5beta1 and alphavbeta3 integrins. However, the signaling pathways linking Tat to the regulation of cellular functions are incompletely understood. Here, we report that Tat ligation on human endothelial cells results in the activation of the small GTPases Ras and Rac and the mitogen-activated protein kinase ERK, specifically through its RGD region. In addition, we demonstrated that Tat activation of Ras, but not of Rac, induces ERK phosphorylation. We also found that the receptor proximal events accompanying Tat-induced Ras activation are mediated by tyrosine phosphorylation of Shc and recruitment of Grb2. Moreover, Tat enabled endothelial cells to progress through the G1 phase in response to bFGF, and the process is linked to ERK activation. Taken together, these data provide novel evidence about the ability of Tat to activate the Ras-ERK cascade which may be relevant for endothelial cell proliferation and for Kaposi's sarcoma progression.
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PMID:HIV-1 Tat regulates endothelial cell cycle progression via activation of the Ras/ERK MAPK signaling pathway. 1643 5

Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. KSHV infection of cells produces both latent and lytic cycles of infection. In vivo, the virus is found predominantly in the latent state. In vitro, a lytic infection can be induced in KSHV-infected cells by treating with phorbol ester (TPA). However, the exact signalling events that lead to the reactivation of KSHV lytic infection are still elusive. Here, a role is demonstrated for B-Raf/MEK/ERK signalling in TPA-induced reactivation of KSHV latent infection. Inhibiting MEK/ERK signalling by using MEK-specific inhibitors decreased expression of the TPA-induced KSHV lytic-cycle gene ORF8. Transfection of BCBL-1 cells with B-Raf small interfering RNA inhibited TPA-induced KSHV lytic infection significantly. Additionally, overexpression of MEK1 induced a lytic cycle of KSHV infection in BCBL-1 cells. The significance of these findings in understanding the biology of KSHV-associated pathogenesis is discussed.
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PMID:Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency. 1660 14

The histogenesis of Kaposi's sarcoma (KS) tumor spindle cells (SC) remains controversial but several immunohistochemical studies favor a lymphatic origin. Twenty KS surgical biopsies were analyzed for the coexpression of LANA, CD34, LYVE-1, D2-40, VEGFR-2, VEGFR3 by using double or triple immunostaining. Most of the SC in both early and late KS expressed the lymphatic markers LYVE-1, D2-40 and VEGFR-3 and the blood vascular endothelial/endothelial precursor cell markers CD34 and endothelial stem cell marker VEGFR-2. All the LANA+ SC in early and late KS were LYVE-1+, but only 75% of these LANA+ cells were CD34(+). The CD34(+)/LANA+ cells increased from early- (68.8%) to late-stage KS (82.2%). However, approximately 18% of the LANA+ SC in early KS were CD34(-) but were LYVE-1+, suggesting that resident lymphatic endothelial cells (LEC) are targeted for primary infection by human herpesvirus-8. This LANA+/LYVE-1+/CD34(-) (resident LEC) cell population clearly decreased during the development of KS from early (18.7%) to late KS (2.9%). Thus, in late stages of KS, most SC were LANA+/CD34(+)/LYVE-1+. However, in both early- and late-stage KS, approximately 18% of the SC were CD34(+)/LANA-/LYVE-1 -- and could represent newly recruited endothelial precursor cells, which become infected in the lesion and eventually undergo a phenotype switch expressing LEC markers. Our study apparently indicates that KS represents a unique variant of tumor growth with continues recruitment of tumor precursor cells as well as proliferation and decreased apoptosis of SC.
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PMID:Lymphatic and vascular origin of Kaposi's sarcoma spindle cells during tumor development. 1661 15

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma, a dominant AIDS-related tumor of endothelial cells, and several other lymphoproliferative malignancies. While activation of the phosphatidylinositol 3-kinase-protein kinase C-MEK-ERK pathway is essential for KSHV infection, we have recently shown that KSHV also activates JNK and p38 mitogen-activated protein kinase (MAPK) pathways during primary infection (J. Xie, H. Y. Pan, S. Yoo, and S.-J. Gao, J. Virol. 79:15027-15037, 2005). Here, we found that activation of both JNK and p38 pathways was also essential for KSHV infection. Inhibitors of all three MAPK pathways reduced KSHV infectivity in both human umbilical vein endothelial cells (HUVEC) and 293 cells. These inhibitory effects were dose dependent and occurred at the virus entry stage of infection. Consistently, inhibition of all three MAPK pathways with dominant-negative constructs reduced KSHV infectivity whereas activation of the ERK pathway but not the JNK and p38 pathways enhanced KSHV infectivity. Importantly, inhibition of all three MAPK pathways also reduced the yield of infectious virions during KSHV productive infection of HUVEC. While the reduction of infectious virions was in part due to the reduced infectivity, it was also the result of direct modulation of KSHV lytic replication by the MAPK pathways. Accordingly, KSHV upregulated the expression of RTA (Orf50), a master transactivator of KSHV lytic replication, and activated its promoter during primary infection. Furthermore, KSHV activation of RTA promoter during primary infection was modulated by all three MAPK pathways, predominantly through their downstream target AP-1. Together, these results indicate that, by modulating multiple MAPK pathways, KSHV manipulates the host cells to facilitate its entry into the cells and postentry productive lytic replication during primary infection.
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PMID:Modulation of Kaposi's sarcoma-associated herpesvirus infection and replication by MEK/ERK, JNK, and p38 multiple mitogen-activated protein kinase pathways during primary infection. 1669 17

Kaposi's sarcoma (KS) is an angioproliferative neoplasia associated with human herpesvirus 8 (HHV-8) infection. HHV-8 generates KS by means of the secretion of vascular endothelial growth factor (VEGF) andup-regulation of VEGF receptor, KDR, in endothelial cells. We report a case of KS in a 72-year-old male with a renal transplant who had received immunosuppressant drugs including sirolimus, mycophenolate mofetil, tacrolimus and steroids. KS developed 11 months after transplantation, in relation to deep venous thrombosis and withdrawal of sirolimus due to toxicity. Multiple purple papules and nodules were observed exclusively in the limb affected by thrombosis. Diagnosis of KS was confirmed by biopsy. Progressive withdrawal of prednisone was accompanied by full remission of the tumour. The thrombosis and withdrawal of sirolimus may have acted as cofactors in the development of KS, favouring the activation of the VEGF/KDR autocrine loop. Our experience contributes to further evidence that sirolimus may protect against KS.
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PMID:Posttransplant Kaposi's sarcoma restricted to the site of a previous deep venous thrombosis: abrupt onset after withdrawal of sirolimus. 1677 18

Cytogenetic discoveries of balanced translocations in soft tissue tumors have opened the way to molecular genetic definition of these translocations as gene fusions from the late 1980s. Many sarcomas are known to have such fusions, and the demonstration of the fusion transcripts in tumor tissue is of great value in specific diagnosis of synovial sarcoma (SYT-SSX), Ewing sarcoma (EWS-Fli1), clear cell sarcoma (EWS-ATF1), myxoid liposarcoma (FUS-CHOP), and other sarcomas. These translocations are believed to be disease-specific and pathogenetic forces, despite occasional observations to the contrary. Demonstration of SYT-SSX and EWS-ATF1 fusion assists in the diagnosis of synovial and clear cell sarcomas in unusual locations, such as the gastrointestinal tract, where these tumors occur with low frequency. Demonstration of sarcoma translocations and their fusion by different assays is well established; use of in situ hybridization is limited by availability of specific probes. In two exceptional instances, the same translocation and gene fusion occurs in two unrelated diseases: ETV6-NTRK fusion in infantile fibrosarcoma and secretory carcinoma of the breast, and ALK-TPM3 fusion in inflammatory myofibroblastic tumor and large cell anaplastic lymphoma. Thus, the target cell of the genetic change is an important factor to define the resulting disease. Activating mutations in two related receptor tyrosine kinases (RTKs), KIT, and platelet-derived growth factor receptor alpha (PDGFRA) is central to the pathogenesis of gastrointestinal stromal tumors (GISTs), and countering the mutational activation by specific tyrosine kinase inhibitors, such as Imatinib mesylate, is now standard treatment for metastatic GISTs. KIT exon 11 mutations (in frame deletions, point mutations, and duplications) occur in GISTs of all locations, whereas a characteristic exon 9 insertion-duplication AY502-503 is nearly specific for intestinal vs gastric tumors. In contrast, PDGFRA mutations are nearly specific for gastric GISTs, especially those with epithelioid morphology. Mutation type influences therapy responsiveness, but fortunately very few GISTs carry primarily Imatinib-resistant mutations. Secondary drug resistance acquired during Imatinib treatment based on new, Imatinib-resistant mutations is a major problem limiting treatment success. Loss of NF2 tumor suppressor gene in a biallelic fashion is believed to be central in the pathogenesis of neurofibromatosis 2 (NF2) associated and sporadic schwannomas and meningiomas. The mechanism includes nonsense or missense mutation in NF2 gene, and loss of the other NF2 allele as a part of losses in chromosome 22q. Schwannoma types may differ in their pathogenesis: gastrointestinal schwannomas lack NF2 changes suggesting a different pathogenesis. Intraneural and sclerosing perineuriomas display similar NF2 gene alterations as seen in meningioma, indicating a similar pathogenesis and molecular homology. Specific viral sequences of human herpesvirus 8 (HHV8) are diagnostic markers for Kaposi sarcoma (KS), and are absent in angiosarcoma. Despite discovery on simian virus SV40 sequences in mesothelioma as a possible pathogenetic factor, recent studies suggest that the presence of these sequences may be artifactual and based on common presence of some SV40 sequences as PCR contaminants.
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PMID:From morphological to molecular diagnosis of soft tissue tumors. 1716 60

Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is required for the development of Kaposi's sarcoma (KS), a highly inflammatory angiogenic tumor of endothelial cells commonly found in untreated AIDS patients. Angiopoietin 2 (Ang-2) modulates the vasculature during inflammation and angiogenesis, but the mechanism by which KSHV regulates Ang-2 expression has not been investigated. Here, we show that KSHV infection of primary human umbilical vein endothelial cells induced the expression and release of Ang-2, which in turn was required for KSHV-induced paracrine-dependent angiogenesis in vivo. Ang-2 was strongly expressed in small vessels and spindle tumor cells in KS tumors. Mechanistically, KSHV activated the Ang-2 promoter via AP-1 and Ets1 transcriptional factors, which were mediated by ERK, JNK, and p38 mitogen-activated protein kinase (MAPK) pathways. Our findings demonstrate the importance of Ang-2 in KS angiogenesis and define a novel role for AP-1 and MAPK pathways in regulating angiogenesis. This study also illustrates a distinct mechanism by which a tumor virus modulates vasculature to promote tumorigenesis and exemplifies the convergence of oncogenesis and angiogenesis pathways in tumor development.
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PMID:Kaposi's sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and Ets1. 1728 78

The herpesvirus life cycle has two distinct phases: latency and lytic replication. The balance between these two phases is critical for viral pathogenesis. It is believed that cellular signals regulate the switch from latency to lytic replication. To systematically evaluate the cellular signals regulating this reactivation process in Kaposi sarcoma-associated herpesvirus, the effects of 26,000 full-length cDNA expression constructs on viral reactivation were individually assessed in primary effusion lymphoma-derived cells that harbor the latent virus. A group of diverse cellular signaling proteins were identified and validated in their effect of inducing viral lytic gene expression from the latent viral genome. The results suggest that multiple cellular signaling pathways can reactivate the virus in a genetically homogeneous cell population. Further analysis revealed that the Raf/MEK/ERK/Ets-1 pathway mediates Ras-induced reactivation. The same pathway also mediates spontaneous reactivation, which sets the first example to our knowledge of a specific cellular pathway being studied in the spontaneous reactivation process. Our study provides a functional genomic approach to systematically identify the cellular signals regulating the herpesvirus life cycle, thus facilitating better understanding of a fundamental issue in virology and identifying novel therapeutic targets.
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PMID:Systematic identification of cellular signals reactivating Kaposi sarcoma-associated herpesvirus. 1739 60

The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) protein is functionally pleiotropic. LANA contributes to KSHV-associated pathogenesis, in part, by increasing entry of cells into S phase through a process that is driven by LANA interaction with the serine-threonine kinase glycogen synthase kinase 3 (GSK-3) and stabilization of beta-catenin. We now show that LANA affects the activity of another protein involved in cell cycle regulation, c-Myc. Sequencing of c-Myc coding sequences revealed that c-Myc in KSHV-positive primary effusion lymphoma (PEL) cell lines is wild type in the N-terminal region that regulates c-Myc protein stability. Despite this, c-Myc in PEL cells is stabilized. In LANA-expressing cells, inactivation of nuclear GSK-3 reduced phosphorylation of c-Myc at Thr58 and contributed to c-Myc stabilization by decreasing c-Myc ubiquitination. Phosphorylation of c-Myc on Ser62 also affects c-Myc stability and function. We now show that LANA increases the level of phosphorylated extracellular signal-regulated kinase 1 (ERK1) and increases ERK phosphorylation of c-Myc on Ser62. LANA also interacted with c-Myc, and c-Myc amino acids 147 to 220 were required for this interaction. LANA (L1006P) retained the ability to bind to c-Myc and activate ERK1, indicating that these events did not require LANA interaction with GSK-3. Thus, LANA stabilizes c-Myc; prevents the phosphorylation of c-Myc at Thr58, an event that promotes Myc-induced apoptosis; and independently stimulates phosphorylation of c-Myc at Ser62, an event that transcriptionally activates c-Myc. LANA-mediated manipulation of c-Myc function is likely to contribute to KSHV-associated tumorigenesis through the induction of c-Myc regulated cellular genes, as well as by the stimulation of cell cycle progression.
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PMID:The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc. 1763 26


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