Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma

Annunziata, Christina M.; Davis, R. Eric; Demchenko, Yulia N.; Bellamy, William; Gabrea, Ana; Zhan, Fenghuang; Lenz, Georg; Hanamura, Ichiro; Wright, George W.; Xiao, Wenming; Davé, Sandeep S.; Hurt, Elaine M.; Tan, Bruce K.; Zhao, Hong; Stephens, Owen; Santra, Madhumita; Williams, D.; Dang, Lenny; Barlogie, Bart; Shaughnessy, John D.; Kuehl, W. Michael; Staudt, Louis M.

doi:10.1016/j.ccr.2007.07.004

Cited by 887 publications

(961 citation statements)

References 55 publications

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“…However, in multiple myeloma and other hematologic malignancies, no mutations have been identified in the Wnt/b-catenin pathway, indicating alternative mechanisms for b-catenin activation (Derksen et al, 2004;Qiang et al, 2005;Sukhdeo et al, 2007). Interestingly CYLD expression is downregulated in multiple myeloma (Annunziata et al, 2007), suggesting that similarly to our model, reduced CYLD activity could cause activation of b-catenin in this type of cancer.…”

Section: Discussionsupporting

confidence: 52%

“…Additional studies have associated Cyld downregulation with the development of other types of human cancer including tumors of colon, lung and kidney, as well as melanomas and cervical and hepatocellular carcinomas (Strobel et al, 2002;Hashimoto et al, 2004;Hirai et al, 2004;Costello et al, 2005;Hellerbrand et al, 2007;Keats et al, 2007;Zhong et al, 2007;Massoumi et al, 2009). In the case of multiple myeloma and melanoma, it has been shown that its grade of malignancy is directly related with the silencing of CYLD, being of poor prognosis those tumors with lower expression level of CYLD (Annunziata et al, 2007;Jenner et al, 2007;Massoumi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Here, we have focused our attention to the study of the possible involvement of CYLD in skin tumor progression, as this gene has been implicated in the progression of different cancer cell types such as melanoma, colon, hepatocellular and multiple myeloma (Annunziata et al, 2007;Hellerbrand et al, 2007;Jenner et al, 2007;Massoumi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

et al. 2010

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In this study, we demonstrate that the expression in tumorigenic epidermal cells of a catalytically inactive form of CYLD (CYLD C/S ) that mimics the identified mutations of cyld in human tumors and competes with the endogenous CYLD results in enhanced cell proliferation and inhibition of apoptosis; it also stimulates cell migration and induces the expression of angiogenic factors, including vascular endothelial growth factor-A. Altogether, these characteristics indicate an increased oncogenicity of the tumorigenic epidermal CYLD C/S mutant cells in vitro. Moreover, we show the increase in malignancy of epidermal squamous cell carcinomas that express the CYLD C/S transgene in an in vivo xenograft model. Tumors carrying the mutated CYLD C/S exhibit a fast growth, are poorly differentiated and present a robust angiogenesis. CYLD C/S tumors are also characterized by their elevated proliferation rate and decreased apoptosis. In contrast with previous studies showing the development of benign tumors by mutations in the CYLD gene, here we provide evidence that the occurrence of mutations in the CYLD gene in tumorigenic epidermal cells (carrying previous mutations) increases the aggressiveness of carcinomas, mainly through enhancement of the expression of angiogenic factors, having therefore a key role in epidermal cancer malignancy.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

et al. 2010

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“…Finally, it is remarkable that components of the non-canonical pathway, such as LTβR, NIK, or NFκB2, are more often found to be mutated or misregulated in multiple myeloma than components of the canonical NF-κB pathway. Inhibition of this hyperactivated non-canonical pathway indeed led to growth arrest and cell death in vitro (Annunziata et al, 2007;Keats et al, 2007).…”

Section: Implication Of the Signaling Crosstalk In Diseasementioning

confidence: 95%

Crosstalk via the NF-κB signaling system

Basak¹,

Hoffmann²

2008

Cytokine & Growth Factor Reviews

150

114

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The NF-κB family of transcription factors consists of fifteen possible dimers whose activity is controlled by a family of inhibitor proteins, known as IκBs. A variety of cellular stimuli, many of them transduced by members of the TNFR superfamily, induce degradation of IκBs to activate an overlapping subset of NF-κB dimers. However, generation and stimulus-responsive activation of NF-κB dimers are intimately linked via various cross-regulatory mechanisms that allow crosstalk between different signaling pathways through the NF-κB signaling system. In this review, we summarize these mechanisms and discuss physiological and pathological consequences of crosstalk between apparently distinct inflammatory and developmental signals. We argue that a systems approach will be valuable for understanding questions of specificity and emergent properties of highly networked cellular signaling systems.

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“…In MM, both classical and the alternative pathways were reported to be active due to various mutations 23,24 . Among these, mutations in the genes encoding TRAF3, TRAF2 and combined loss of cIAP1 and cIAP2 leading to the stabilization and activation of NIK, were frequently found in MM 24 .…”

mentioning

confidence: 99%

Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

et al. 2015

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Although transcriptional activation by NF-kB is well appreciated, physiological importance of transcriptional repression by NF-kB in cancer has remained elusive. Here we show that an HDAC4-RelB-p52 complex maintains repressive chromatin around proapoptotic genes Bim and BMF and regulates multiple myeloma (MM) survival and growth. Disruption of RelB-HDAC4 complex by a HDAC4-mimetic polypeptide blocks MM growth. RelB-p52 also represses BMF translation by regulating miR-221 expression. While the NIK-dependent activation of RelB-p52 in MM has been reported, we show that regardless of the activation status of NIK and the oncogenic events that cause plasma cell malignancy, several genetically diverse MM cells including Bortezomib-resistant MM cells are addicted to RelB-p52 for survival. Importantly, RelB is constitutively phosphorylated in MM and ERK1 is a RelB kinase. Phospho-RelB remains largely nuclear and is essential for Bim repression. Thus, ERK1-dependent regulation of nuclear RelB is critical for MM survival and explains the NIK-independent role of RelB in MM.

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Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma

Cited by 887 publications

References 55 publications

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

Crosstalk via the NF-κB signaling system

Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

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