The Inhibitor of Death Receptor Signaling, Flice-Inhibitory Protein Defines a New Class of Tumor Progression Factors

Djerbi, Mounira; Screpanti, Valentina; Catrina, Anca I.; Bogen, Bjarne; Biberfeld, Peter; Grandien, Alf

doi:10.1084/jem.190.7.1025

Cited by 387 publications

(285 citation statements)

References 25 publications

(33 reference statements)

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“…Many of the proteins encoded by HHV-8 may also inhibit immune responses to the virus. For example, vFLIP blocks cytotoxic T-cell killing of HHV-8-infected cells by inhibiting Fas activation [43]; vMIP-II may restrict recruitment of Th1 lymphocytes to HHV-8-infected cells [44]; K1 may prevent class 2 MHC-mediated T cell activation by HHV-8 [45]; and K3 and K5 block cell surface display of class 1 MHC molecules on the cell surface [46]. Although the majority of cells within KS lesions show latent infection, a small subset expresses lytic cycle genes [47] and produce viral progeny [48].…”

Section: The Role Of Hhv-8mentioning

confidence: 99%

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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Interferon alfa (IFNA) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFNα in KS treatment, little is currently known about the mechanism(s) by which IFNA causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFNA activities. To a large extent other agents have supplanted IFNA as treatments for KS, but there may still remain a therapeutic role for IFNA, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling. KeywordsInterferon; Kaposi's sarcoma In 1995, when I was honored as a recipient of the ISICR Milstein Award, the AIDS epidemic had recently begun its 15 th year and the human immunodeficiency virus (HIV-1) had been isolated some 12 years previously [1]. However, the virus associated with Kaposi's sarcoma (KS), the most common AIDS-associated malignancy, had been described less than a year earlier [2], its significance was still in some question and its role in KS development had not been characterized, and the active combination drug regimens with which we now treat HIV infection had not yet become widely available. Recombinant interferon alfa preparations (IFNα2a and IFNα2b), which had received approval from the U.S. Food and Drug Administration (FDA) for treatment of AIDS-associated KS in 1988, were still the only approved drugs for systemic treatment of KS (the chemotherapeutic agent, liposomal doxorubicin, would receive FDA approval later in 1995, as did liposomal daunorubicin in 1996 and paclitaxel in 1997). Now, more than a quarter century after the first published reports describing AIDS and its association with KS [3-6] and our first modestly successful attempts to treat KS with IFNα [7], this agent is used infrequently to treat KS, although it still finds use in HIV-infected individuals co-infected with hepatitis C. In this brief review, I will summarize some of the history of IFNα in the treatment of AIDS-associated KS, concentrating on examples of clinical trials in which I have personally been involved, and consider whether there remains a potentially valuable role for this agent in KS treatment.

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Section: The Role Of Hhv-8mentioning

confidence: 99%

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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“…Intracellular inhibition of CD95 apoptosis signaling by FLIP has been shown to favor tumor immune escape and to act as a tumor progression factor [13,14]. Although FLIP S efficiently inhibits CD95-mediated apoptosis, lck FLIP S -transgenic mice did not develop T cell lymphomas within their normal lifetime.…”

Section: Transgenic Overexpression Of Flip S Does Not Lead To Tumorigmentioning

confidence: 99%

“…Thus, c-FLIP L expression in tumor cells has been correlated with resistance to CD95-induced apoptosis in vitro and enhanced tumor progression in vivo [13,14].…”

Section: Introductionmentioning

confidence: 99%

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

et al. 2005

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The cellular homologues of the viral anti-apoptotic v-FLIP proteins exist as a long (c-FLIP L ) and a short (c-FLIP S ) splice variant. While c-FLIP S and v-FLIP are composed solely of two death effector domains, c-FLIP L contains an (inactive) caspase-like domain in addition to these two death effector domains, thereby structurally resembling proCaspase-8. Both c-FLIP L and c-FLIP S suppress apoptosis by inhibiting Caspase-8 activation, although at different levels of pro-Caspase-8 processing. To analyze the consequences of deregulated c-FLIP S expression in vivo, we established lck FLIP Stransgenic mice overexpressing the transgene in thymocytes and in mature T cells. As expected, CD95L-induced apoptosis was impaired in lck FLIP S -transgenic T cells, indicating the functionality of the FLIP S transgene. Remarkably, activation-induced cell death of transgenic T cells was unaffected, despite the observed inhibition of CD95-induced T cell death. Thymic and splenic cell numbers as well as CD4/CD8 cellularity were normal in lck FLIP S -transgenic animals, which in contrast to CD95-deficient mice do not accumulate Thy1 + B220 + CD4 -CD8 -peripheral T cells. c-FLIP S overexpression leads to a significant decrease in activation-induced T cell proliferation in vitro. Despite the capacity of FLIP S to inhibit CD95-induced apoptosis, T cell lymphomagenesis is not observed in lck FLIP S -transgenic mice. Interestingly, the Vb8 + memory T cell pool is enlarged upon staphylococcal enterotoxin B injections, suggesting a specific in vivo function for FLIP S in the maintenance of restimulated T cells. IntroductionAmong many anti-apoptotic regulatory proteins, the Caspase-8-inhibitory FLIP molecule has been studied intensively. Originally detected in different viruses, c-FLIP was eventually identified as the cellular homologue of the v-FLIP proteins ([1, 2] and references herein). Several spliced isoforms of c-FLIP have been characterized, two of which are expressed as proteins: c-FLIP L , the full-length 55-kDa form of c-FLIP, comprises two Nterminal death effector domains (DED) and an enzymatically inactive caspase domain, thereby structurally resembling . c-FLIP S is a shorter 26-kDa form of c-FLIP and, like v-FLIP, contains only the two DED.A functional pro-apoptotic death-inducing signaling complex (DISC) is usually assembled by recruitment of the adaptor protein FADD to the activated CD95 receptor via death domain interactions [3]. Due to binding of their DED, FADD then associates Caspase-8 Molecular immunologyThe first two authors contributed equally to this work. [2,5]. Recruitment of both c-FLIP L and c-FLIP S to the activated intracellular CD95 receptor complex by FADD has been demonstrated, and both proteins are able to inhibit CD95-induced apoptosis as well as cell death mediated by other death receptors [6]. It has even been suggested that c-FLIP S rather than c-FLIP L may be the prime inhibitor of CD95-mediated apoptosis in T cells [7]. Nevertheless, a recent study showed that whereas high levels of c-FLIP L o...

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“…To impact the role of pro-survival proteins known to be NF-kB targets, we examined the expression of FLICE-inhibitory protein (FLIP) (Micheau et al, 2001) whose elevated expression has been shown to promote tumor establishment (Djerbi et al, 1999;Medema et al, 1999) and of members of the IAP family frequently overexpressed in tumors, i.e. IAP1, IAP2 and XIAP.…”

Section: Resultsmentioning

confidence: 99%

Activation of the NF-κB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKα

et al. 2006

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The Inhibitor of Death Receptor Signaling, Flice-Inhibitory Protein Defines a New Class of Tumor Progression Factors

Cited by 387 publications

References 25 publications

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Activation of the NF-κB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKα

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The Inhibitor of Death Receptor Signaling, Flice-Inhibitory Protein Defines a New Class of Tumor Progression Factors

Cited by 387 publications

References 25 publications

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Transgenic overexpression of the Caspase‐8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Activation of the NF-κB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKα

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Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection