Differential expression of active mitogen-activated protein kinase in cutaneous endothelial neoplasms: Implications for biologic behavior and response to therapy

Arbiser, Jack L.; Weiss, Sharon W.; Arbiser, Zoya K.; Bravo, Francisco; Govindajaran, Baskaran; H, Cáceres-Ríos; Cotsonis, George; Recavarren, Sixto; Swerlick, Robert A.; Cohen, Cynthia

doi:10.1067/mjd.2000.111632

Cited by 43 publications

(36 citation statements)

References 27 publications

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“…We hypothesized that MAPK is activated in tumors that are deficient in p16ink4a (11)(12)(13)(14)(15)(16). To test this hypothesis, we assessed the status of MAPK activation in BL cell lines.…”

Section: Ebv-positive Bl Cell Lines Show Activation Of Mapk Signalingmentioning

confidence: 99%

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Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

Cerimele

Battle²,

Lynch³

et al. 2004

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

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135

137

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Burkitt's lymphoma (BL) is an aggressive B cell neoplasm, which is one of the most common neoplasms of childhood. It is highly widespread in East Africa, where it appears in endemic form associated with Epstein-Barr virus (EBV) infection, and around the world in a sporadic form in which EBV infection is much less common. In addition to being the first human neoplasm to be associated with EBV, BL is associated with a characteristic translocation, in which the Ig promoter is translocated to constitutively activate the c-myc oncogene. Although many BLs respond well to chemotherapy, a significant fraction fails to respond to therapy, leading to death. In this article, we demonstrate that EBV-positive BL expresses high levels of activated mitogen-activated protein kinase and reactive oxygen species (ROS), and that ROS directly regulate NF-B activation. EBV-negative BLs exhibit activation of phosphoinositol 3-kinase, but do not have elevated levels of ROS. Elevated reactive oxygen may play a role in diverse forms of viral carcinogenesis in humans, including cancers caused by EBV, hepatitis B, C, and human T cell lymphotropic virus. Our findings imply that inhibition of ROS may be useful in the treatment of EBVinduced neoplasia.angiogenesis B urkitt's lymphoma (BL) is a distinct neoplasm of B lymphocytes characterized by a translocation of the Ig heavy-or light-chain promoter and enhancer elements into the c-myc oncogene (1). This neoplasm is also of historic interest, because a technician who developed infectious mononucleosis became seropositive for Epstein-Barr virus (EBV), thus establishing a role of EBV in both acute infectious mononucleosis and BL (1). Since the recognition of a causative role of EBV in infectious mononucleosis, EBV has been implicated in other neoplastic disorders, including nasopharyngeal carcinoma, transplantrelated lymphoproliferative disorder, Hodgkins disease, gastric cancer, and cutaneous leiomyosarcoma in patients with AIDS (2-9).BL is characterized by EBV-positive and -negative phenotypes, which occur in distinct epidemiological subgroups. Endemic BL, which was first characterized as a childhood neoplasm in East Africa, is characterized by rapidly growing tumors of the mandible. EBV-positive BL also occurs at a high frequency in iatrogenically immunosuppressed patients as well as patients who are positive for HIV. Although BLs are often highly responsive to conventional chemotherapy, severe preexisting immunosuppression and other comorbid conditions often prevent full use of chemotherapy in these patients (10).We have previously hypothesized that tumors that exhibit loss of the tumor suppressor genes p16ink4a and͞or p53 also exhibit distinct and predictable patterns of signal transduction pathway dependence (11,12). Based on prior results from our laboratory, we have demonstrated synergy between inactivation of p16ink4a and activation of mitogen-activated protein kinase (MAPK) (13-15). Also, we have found that cancers caused by reactive oxygen species (ROS) demonstrate high levels of hyp...

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Section: Ebv-positive Bl Cell Lines Show Activation Of Mapk Signalingmentioning

confidence: 99%

“…Based on prior results from our laboratory, we have demonstrated synergy between inactivation of p16ink4a and activation of mitogen-activated protein kinase (MAPK) (13)(14)(15). Also, we have found that cancers caused by reactive oxygen species (ROS) demonstrate high levels of hypermethylation of the tumor suppressor p16ink4a and activation of MAPK (16).…”

mentioning

confidence: 99%

Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

Cerimele

Battle²,

Lynch³

et al. 2004

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

Self Cite

135

137

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show abstract

“…However another immunohistochemistry study of benign and malignant vascular tumours suggested pERK was significantly lower in malignant endothelial lesions [200]. There was also evidence to support the study of MEK …”

Section: Mek Inhibitionmentioning

confidence: 86%

Vascular-targeted agents for the treatment of angiosarcoma

Young

Woll

Staton

et al. 2013

Cancer Chemother Pharmacol

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“…5 Furthermore, MAPKs are often associated with pathologic responses, such as stress, apoptosis, inflammation, and cell proliferation. 5,6 In terms of vascular conditions, differential expression of active MAPKs was noticed in several types of hemangiomas, 7 the most common vascular tumor of infancy and childhood, 8 and the presence of immunoreactive phosphorylated MAPK inversely correlate with degree of malignancy. 7 Therefore, from a drug discovery standpoint, vascular specific components of MAPKs cascade are promising drug targets.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 In terms of vascular conditions, differential expression of active MAPKs was noticed in several types of hemangiomas, 7 the most common vascular tumor of infancy and childhood, 8 and the presence of immunoreactive phosphorylated MAPK inversely correlate with degree of malignancy. 7 Therefore, from a drug discovery standpoint, vascular specific components of MAPKs cascade are promising drug targets. 6 MAPKs are activated by dual phosphorylation of tyrosine and threonine residues in their activation loops.…”

Section: Introductionmentioning

confidence: 99%

Dusp-5 and Snrk-1 coordinately function during vascular development and disease

Pramanik

Chun

Garnaas

et al. 2009

Blood

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IntroductionThe mitogen-activated protein kinase (MAPK) pathway 1 represent a key signal integration step inside the cell for various extracellular stimuli. 2 At least 4 MAPK families have been identified: the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and Erk5. Each MAPK is activated by specific MAPK kinases (Mkks or Meks), which in turn are regulated by Mek kinases (Mekks). To date, several members of the MAPK family, including Erk5 3 and Mekk3, 4 have been implicated in vascular development in vivo. 5 Furthermore, MAPKs are often associated with pathologic responses, such as stress, apoptosis, inflammation, and cell proliferation. 5,6 In terms of vascular conditions, differential expression of active MAPKs was noticed in several types of hemangiomas, 7 the most common vascular tumor of infancy and childhood, 8 and the presence of immunoreactive phosphorylated MAPK inversely correlate with degree of malignancy. 7 Therefore, from a drug discovery standpoint, vascular specific components of MAPKs cascade are promising drug targets. 6 MAPKs are activated by dual phosphorylation of tyrosine and threonine residues in their activation loops. To control MAPK activation, a family of proteins called dual-specificity protein tyrosine phosphatases (DUSPs) dephosphorylate both residues. 9 DUSPs come in 2 varieties: dual-specificity MAPK phosphatases and atypical DUSPs. A dual specific phosphatase, Dusp-5, was recently identified by 2 independent microarray studies as a vascular-specific gene, 10,11 and we hypothesized that dusp-5 plays a specific role in vascular development. To investigate dusp-5 function, we initiated a loss-of-function (LOF) study in zebrafish (ZF). We identified that dusp-5 LOF embryos showed enhanced etsrp ϩ angioblasts at the lateral plate mesoderm (LPM). Recently, we had identified in a gain-of-function (GOF) and LOF study for a serine-threonine kinase member of the sucrose nonfermenting kinase family, Snrk-1, that it increased or decreased, respectively, the same etsrp ϩ angioblast population at the LPM. 12 Taking these findings together, we hypothesized that, during vascular development, Dusp-5 and Snrk-1 function together in controlling angioblast numbers at the LPM. In this study, we show that dusp-5 is expressed in angioblasts in the embryonic ZF and is essential for vascular development in vivo. We show that loss of Dusp-5 function in vitro causes apoptosis of endothelial cells (ECs), and Dusp-5 and Snrk-1 target a common signaling pathway responsible for maintaining angioblast populations along the LPM. Snrk-1 ectopically induces etsrp ϩ angioblasts in the LPM, which is blocked by Dusp-5 that functions downstream of Snrk-1. In addition, we have identified mutations in dusp-5 and snrk-1 in the lesional tissue of many vascular anomaly patient samples, suggesting a critical role for this pathway in disease. Methods ZF stocksWild-type ZF (TuAB strain) were grown and maintained at 28.5°C. 13 All procedures were performed according to animal protoc...

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Differential expression of active mitogen-activated protein kinase in cutaneous endothelial neoplasms: Implications for biologic behavior and response to therapy

Cited by 43 publications

References 27 publications

Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

Vascular-targeted agents for the treatment of angiosarcoma

Dusp-5 and Snrk-1 coordinately function during vascular development and disease

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