Dataset Information

Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-?B activation in diffuse large B-cell lymphoma.

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and nuclear factor (NF)-?B pathways is ubiquitously observed and known to mediate tumor growth, survival, and chemoresistance in DLBCL. Here, we find that activation of Hh signaling is positively correlated with NF-?B pathway in DLBCL tumors, and that smoothened (SMO), the signal transducer subunit of Hh pathway, contributes to NF-?B activation through recruiting G protein subunits G?i and G?12 to activate PKC?/CARMA1/TRAF6/NEMO signaling axis followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO. Moreover, functional inhibition of SMO enhances the cytotoxic effects of NF-?B inhibitor. Altogether, our study reveals a noncanonical Hh signaling pathway in which SMO activates trimeric G proteins and CARMA1-associated signaling complex, leading to NF-?B activation. This signaling cascade contributes to the survival of DLBCL and may serve as a potential target for combination therapies in DLBCL.

SUBMITTER: Qu C

PROVIDER: S-EPMC3674670 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-κB activation in diffuse large B-cell lymphoma.

Qu Changju C Liu Yadong Y Kunkalla Kranthi K Singh Rajesh R RR Blonska Marzenna M Lin Xin X Agarwal Nitin Kumar NK Vega Francisco F

Blood 20130430 23

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and nuclear factor (NF)-κB pathways is ubiquitously observed and known to mediate tumor growth, survival, and chemoresistance in DLBCL. Here, we find that activation of Hh signaling is positively correlated with NF-κB pathway in DLBCL tumors, and that smoothened (SMO), the signal transducer subunit of Hh pathway, contributes to NF-κB activation through recruiting G protein ...[more]

PMID: 23632891

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Project description:Constitutive activation of the anti-apoptotic NF-ÎºB signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) that is characterized by adverse survival. Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-ÎºB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 mutants in the NF-ÎºB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of Î²-Catenin and its destruction complex consisting of APC, AXIN1, CK1Î± and GSK3Î² to oncogenic CARMA1. Recruitment of the Î²-Catenin destruction complex was independent of CARMA1-BCL10-MALT1 (CBM) complex formation or constitutive NF-ÎºB activation and promoted the stabilization of Î²-Catenin. Elevated Î²-Catenin expression was detected in cell lines and biopsies from ABC DLBCL that rely on chronic BCR signaling. Increased Î²-Catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF dependent transcriptional activation in response to WNT signaling. In conjunction with NF-ÎºB, Î²-Catenin enhanced expression of immune suppressive IL-10 and repressed anti-tumoral CCL3, indicating that Î²-Catenin may induce a favorable tumor microenvironment. Thus, parallel activation of NF-ÎºB and Î²-Catenin signaling by gain-of-function mutations in CARMA1 can augment WNT stimulation and is required for maintaining high expression of distinct NF-ÎºB target genes and can thereby trigger cell intrinsic and extrinsic processes that promote DLBCL lymphomagenesis. CARMA1 mutants were expressed in BJAB, an NF-ÎºB negative GCB DLBCL lymphoma cell line. Gene expression induced by GCB DLBCL derived CARMA1 L225LI mutant was compared with the empty vector (mock) control, CARMA1 WT, CARMA1 point mutant R35A and with CARMA1 double mutant R35A/L225LI.

Dataset Information

Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-?B activation in diffuse large B-cell lymphoma.

Publications

Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-κB activation in diffuse large B-cell lymphoma.

Similar Datasets

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