High Expression of MDM2 Protein and Low Rate of p21<sup>WAF1/CIP1</sup> Expression in SCID Mice Epstein Barr Virus-induced Lymphoproliferation

Mansouri, S. El; Martin, Antoine; Mercadier, Anne; Capoulade, Corinne; Maréchal, Vincent; Wiels, Joëlle; Feuillard, Jean; Raphaël, Martine

doi:10.1177/002215549904701011

Cited by 5 publications

(5 citation statements)

References 37 publications

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“…4 The mechanism by which EBV infection leads to lymphoproliferation is not clear, but involves the protection of infected cells from apoptosis, and a recent study indicates that high MDM2 protein expression by EBV infected cells may be important. 6 The apparent localisation of EBV infected lymphocytes to a single region of skin, as seen in our patient, is unusual. It is possible that a preexisting inflammatory or infective focus was responsible for this dermatotropism.…”

Section: Discussionsupporting

confidence: 54%

Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy

Sebire

Haselden²,

Malone³

et al. 2003

Journal of Clinical Pathology

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Patients with primary immunodeficiencies such as the Wiskott-Aldrich syndrome (WAS) are prone to develop Epstein-Barr virus (EBV) related lymphoproliferative disorders (LPDs). EBV LPD is most frequently seen in patients receiving immunosuppressive treatment after organ transplantation (post-transplant lymphoproliferative disorder), but can also arise in the primary immunodeficiencies. Typically, EBV LPD presents as a diffuse systemic disease with lymphadenopathy and organ involvement. A rare angiocentric and angiodestructive form of EBV associated B cell LPD, lymphomatoid granulomatosis (LyG), has also been reported in association with WAS. LyG most commonly involves the lung, but can also be seen in brain, kidney, liver, and skin. This report describes the case of a 16 year old boy with WAS who presented with an isolated non-healing ulcerating skin lesion. Biopsy revealed an EBV related LPD with the histological features of LyG. This cutaneous lesion responded dramatically to treatment with specific anti-CD20 immunotherapy and the patient remains clinically free of LPD at 18 months.A lthough Epstein-Barr virus (EBV) related lymphoproliferative disorders (LPDs) are most frequently seen in patients receiving immunosuppressive treatment after organ transplantation (post-transplant lymphoproliferative disorder; PTLD), they also occur in patients with immunodeficiencies.1 EBV related LPD usually manifests as systemic disease with vague symptomatology, and often shows pulmonary involvement. 2 We present a case of a 16 year old boy with known Wiskott-Aldrich syndrome (WAS) who developed an unusual, non-healing, ulcerating, cutaneous lesion with the clinical and pathological features of lymphomatoid granulomatosis (LyG). Histology confirmed an angiocentric destructive lesion with a mixed infiltrate of T and B cells. The B cells showed nuclear pleomorphism and were EBV positive. There was no evidence of disease elsewhere and this cutaneous lesion responded well to treatment with anti-CD20 immunotherapy. CASE REPORTA 15 year old boy with known WAS presented with an isolated, non-healing, annular 1.5 cm lesion on the left thigh. An initial punch biopsy revealed mild chronic inflammation only, with no specific features, and no organisms could be identified. He remained systemically well but the lesion increased in size to 4 cm and a further incisional biopsy was performed. This showed a focal ulcerating lesion with granulation tissue and fibrosis, and a dense angiocentric lymphocytic infiltrate within the dermis (fig 1). Special stains for fungi, bacteria, and mycobacteria were negative. Immunostaining for CD79a, CD20, CD5, and CD3 demonstrated a mixed T and B cell population, and enabled the identification of a subpopulation of enlarged B cells with moderate nuclear pleomorphism. In situ hybridisation (ISH) for EBV showed highly localised and intense staining for Epstein-Barr encoded viral RNAs (EBERs) in the intralesional lymphocytes, but no positive cells within the surrounding apparently normal skin (fig 1). Polymerase...

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Section: Discussionsupporting

confidence: 54%

Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy

Sebire

Haselden²,

Malone³

et al. 2003

Journal of Clinical Pathology

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“…Mdm2 is known to be overexpressed in numerous human cancers (29,53). Elevated levels of nuclear accumulation of Mdm2 protein were reported previously in EBV-induced lymphoproliferation in severe combined immunodeficient (SCID) mice (18). In an attempt to check the Mdm2 protein expression level in the context of EBV infection and its potent nuclear antigen EBNA3C, EBV-transformed B cells (LCL2) and a Burkitt lymphoma cell line, BJAB cells, stably expressing EBNA3C (two different clones, 7 and 10) were tested along with negative-control BJAB cells.…”

Section: Ebna3c Forms a Complex With Mdm2 Both In Vivo And In Vitromentioning

confidence: 75%

“…Because of its prevalent expression and its interactions with p53 and other signaling molecules, Mdm2 plays a central role in cancer development and progression. Although there are some conflicting data, the overall evidence suggests that EBV infection can lead to an increase in Mdm2 expression (18).…”

Section: Ebna3c Forms a Complex With Mdm2 Both In Vivo And In Vitromentioning

confidence: 99%

Epstein-Barr Virus Nuclear Antigen 3C Augments Mdm2-Mediated p53 Ubiquitination and Degradation by Deubiquitinating Mdm2

Saha

Murakami

Kumar

et al. 2009

J Virol

105

160

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Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) is one of the essential latent antigens for primary B-cell transformation. Previous studies established that EBNA3C facilitates degradation of several vital cell cycle regulators, including the retinoblastoma (pRb) and p27KIP proteins, by recruitment of the SCF Skp2 E3 ubiquitin ligase complex. EBNA3C was also shown to be ubiquitinated at its N-terminal residues. Furthermore, EBNA3C can bind to and be degraded in vitro by purified 20S proteasomes. Surprisingly, in lymphoblastoid cell lines, EBNA3C is extremely stable, and the mechanism for this stability is unknown. In this report we show that EBNA3C can function as a deubiquitination enzyme capable of deubiquitinating itself in vitro as well as in vivo. Functional mapping using deletion and point mutational analysis showed that both the N-and C-terminal domains of EBNA3C contribute to the deubiquitination activity. We also show that EBNA3C efficiently deubiquitinates Mdm2, an important cellular proto-oncogene, which is known to be overexpressed in several human cancers. The data presented here further demonstrate that the N-terminal domain of EBNA3C can bind to the acidic domain of Mdm2. Additionally, the N-terminal domain of EBNA3C strongly stabilizes Mdm2. Importantly, EBNA3C simultaneously binds to both Mdm2 and p53 and can form a stable ternary complex; however, in the presence of p53 the binding affinity of Mdm2 toward EBNA3C was significantly reduced, suggesting that p53 and Mdm2 might share a common overlapping domain of EBNA3C. We also showed that EBNA3C enhances the intrinsic ubiquitin ligase activity of Mdm2 toward p53, which in turn facilitated p53 ubiquitination and degradation. Thus, manipulation of the oncoprotein Mdm2 by EBNA3C potentially provides a favorable environment for transformation and proliferation of EBV-infected cells.

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“…The same group also noted that E2F-1 expression was increased in the pRB/p53/MDM2 (abnormal/+/+) tumors [105]. E2F-1 is a transcription factor MDM2 is overexpressed in Epstein-Barr virus (EBV)infected cells [133] and the protein may be overexpressed upon human papilloma virus (HPV) infection [134]. During HPV infection, the E6 protein downregulates p53, perhaps leaving the pool of MDM2 to interact with its non-p53 signaling partners [135][136][137].…”

Section: Mdm2 In Other Diseasesmentioning

confidence: 99%

MDM2 and Human Malignancies: Expression, Clinical Pathology, Prognostic Markers, and Implications for Chemotherapy

Rayburn

Zhang²,

He³

et al. 2005

CCDT

247

230

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The human homologue of the mouse double minute 2 (MDM2) oncogene is overexpressed in more than forty different types of malignancies, including solid tumors, sarcomas and leukemias. Because of its prevalent expression and its interactions with p53 and other signaling molecules, MDM2 plays a central role in cancer development and progression. The expression of this oncoprotein is being studied by researchers world-wide, and the amount of data published about it is increasing exponentially. Although there are some conflicting data about the effects of MDM2 expression in individual cancers, the overall evidence is convincing, indicating that increased MDM2 expression is related to a worse clinical prognosis. There is an increased likelihood of distant metastases, as well as a decreased response to therapeutic intervention in MDM2-positive cancers. MDM2 may also serve as a diagnostic marker, not only for cancer stage, but to differentiate between similar cancers. MDM2 may also be associated with drug resistance in cancer chemotherapy. These findings make studying the oncoprotein necessary to aid in our understanding of cancer development, to identify novel cancer drug targets, and to increase the efficacy of cancer therapy.

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High Expression of MDM2 Protein and Low Rate of p21^WAF1/CIP1 Expression in SCID Mice Epstein Barr Virus-induced Lymphoproliferation

Cited by 5 publications

References 37 publications

Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy

Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy

Epstein-Barr Virus Nuclear Antigen 3C Augments Mdm2-Mediated p53 Ubiquitination and Degradation by Deubiquitinating Mdm2

MDM2 and Human Malignancies: Expression, Clinical Pathology, Prognostic Markers, and Implications for Chemotherapy

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High Expression of MDM2 Protein and Low Rate of p21WAF1/CIP1 Expression in SCID Mice Epstein Barr Virus-induced Lymphoproliferation

Cited by 5 publications

References 37 publications

Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy

Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy

Epstein-Barr Virus Nuclear Antigen 3C Augments Mdm2-Mediated p53 Ubiquitination and Degradation by Deubiquitinating Mdm2

MDM2 and Human Malignancies: Expression, Clinical Pathology, Prognostic Markers, and Implications for Chemotherapy

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Product

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High Expression of MDM2 Protein and Low Rate of p21^WAF1/CIP1 Expression in SCID Mice Epstein Barr Virus-induced Lymphoproliferation