Shedding and γ-secretase-mediated intramembrane proteolysis of the mucin-type molecule CD43

Andersson, Christian X.; Fernández-Rodrı́guez, Julia; Laos, Sirle; Baeckström, Dan; Haass, Christian; Hansson, Gunnar C.

doi:10.1042/bj20041387

Cited by 39 publications

(35 citation statements)

References 46 publications

(59 reference statements)

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“…This is consistent with the previous findings showing that the cytoplasmic domain of CD43 associates with the cytoskeleton via ERM family adapter proteins (44). The smaller CD43 fragment, supposedly the CD43-CTF that has been shown to migrate at an apparent mass of approximately 20 kDa (in COLO205 cell line slightly higher) (25), was observed in the soluble cytoplasmic fraction, in the membrane fraction and very poorly in the soluble nuclear fraction.…”

Section: Cd43 Requires β-Catenin To Induce P53-dependent Responsesupporting

confidence: 80%

“…When COLO205 cells were incubated with the proteasome inhibitor MG132, the amount of the CD43-CTF increased as previously described (25), and even smaller CD43 fragments could be detected (Fig. 4B).…”

Section: Cd43 Requires β-Catenin To Induce P53-dependent Responsementioning

confidence: 62%

“…org and potential cleavage sites described in (29) and (25)]. The CD43ct has been previously detected by immunoblotting only as a recombinant protein probably due to the rapid degradation of the native form (25). Upon addition of the proteasome inhibitor none of these CD43 molecules translocate to the chromatinbound nuclear fraction; the CD43 fragments appeared only in the fractions where CD43-CTF was present.…”

Section: Cd43 Requires β-Catenin To Induce P53-dependent Responsementioning

confidence: 99%

“…The CD43-CTF which is suggested to be formed by the proteolytic removal of the ectodomain includes a small part of the extracellular domain, the intact transmembrane and intracellular domains. The CD43ct is released as a result of the intramembrane γ-secretase cleavage that follows the cleavage in the extracellular domain (25).…”

Section: Cd43 Requires β-Catenin To Induce P53-dependent Responsementioning

confidence: 99%

“…The translocation of the cytoplasmic part of CD43 to the nucleus is possible due to its γ-secretase-dependent proteolytic removal from the membrane. Human CD43 is processed by γ-secretase in several carcinoma cell lines (25). The resulting CD43 cytoplasmic tail has been shown to localize into a subnuclear structure, known as PML leukaemia nuclear body, and is involved in the regulation of apoptosis (26).…”

Section: Introductionmentioning

confidence: 99%

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Leukocyte marker CD43 promotes cell growth in co-operation with β-catenin in non-hematopoietic cancer cells

et al. 2012

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Abstract. The Wnt/β-catenin pathway regulates key cellular processes such as differentiation, proliferation, apoptosis; and its activation promotes development of several cancer types. Expression of CD43 (leukosialin), the predominant leukocyte transmembrane sialoglycoprotein, has been detected in many tumors of non-hematopoietic origin. CD43 participates in cell adhesion and regulates intracellular signal transduction pathways involved in cell proliferation and survival. The cytoplasmic domain of CD43 has been reported to translocate to the nucleus, interact with β-catenin and affect its target gene expression, but the impact of this action on cell fate is still unknown. We demonstrate, here, by colony formation assay and siRNA-mediated gene silencing that CD43 and β-catenin co-operate in promoting cell growth. Moreover, in cells with down-regulated β-catenin expression the activation of p53 in response to CD43 overexpression is significantly impaired. In addition, the presence of both CD43 and β-catenin is required for the TCF/LEF-mediated transcription. Presumably, the fulllength CD43 participates in this transcriptional regulation. We show that the mature CD43 localizes to the nucleus, where it binds chromatin, co-localizes and co-immunoprecipitates with β-catenin, and enhances the reporter gene expression regulated by β-catenin. These observations provide clear evidence linking CD43 to the Wnt/APC/β-catenin signaling pathway and supporting our hypothesis according to which CD43 plays a role in tumor development.

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Section: Cd43 Requires β-Catenin To Induce P53-dependent Responsesupporting

confidence: 80%

Section: Cd43 Requires β-Catenin To Induce P53-dependent Responsementioning

confidence: 62%

Section: Cd43 Requires β-Catenin To Induce P53-dependent Responsementioning

confidence: 99%

Section: Cd43 Requires β-Catenin To Induce P53-dependent Responsementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Leukocyte marker CD43 promotes cell growth in co-operation with β-catenin in non-hematopoietic cancer cells

et al. 2012

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CD43 in the nucleus and cytoplasm of lung cancer is a potential therapeutic target

Cash

Andersen

et al. 2012

Intl Journal of Cancer

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CD43 is a transmembrane sialoglycoprotein. Normally the molecule is only produced by white blood cells where it regulates functions such as intercellular adhesion, intracellular signaling, apoptosis, migration and proliferation. Two CD43 antibodies were used to interrogate 66 cases of non-small cell lung cancer (NSCLC) and 24 cases of small cell lung cancer (SCLC). In addition, we engineered the CD43-positive lung cancer cell line A549 to stably express either non-targeted or CD43-targeted small-interfering RNA (siRNA). These lines were then subjected to in vitro assays of apoptosis, natural killer (NK) cell cytotoxicity, intercellular adhesion and transendothelial migration. A xenograft mouse model evaluated the ability of the lines to grow primary tumors in vivo. CD43 was found to be expressed in the majority of both SCLC and NSCLC. Inclusive of CD43-negative tumors, differential patterns of nuclear and cytoplasmic expression of CD43 define four molecular subcategories of lung cancer. Targeting CD43 in A549 lung cancer cells, increased homotypic adhesion, decreased heterotypic adhesion and transendothelial migration, increased susceptibility to apoptosis and increased vulnerability to lysis by NK cells. Furthermore, targeting inhibited the growth of primary tumors in nude mice.Despite major advances in the field of medical oncology, lung cancer remains the leading cause of cancer death in the United States among both men and women. With an estimated 221,130 new cases and 156,940 deaths in 2011, lung cancer is responsible for more than 25% of all cancer deaths. 1 Two studies have reported that lung cancer might be characterized by expression of the sialoglycoprotein CD43 normally only produced by leukocytes. 2,3 The first study reported that 13 out of 13 cases of non-small cell lung cancer (NSCLC) expressed CD43 while two out of two cases of small cell lung cancer (SCLC) were CD43-negative. 2 The second study reported that one out of three primary lung tumors exhibited CD43 expression. 3 One of these three tumors was a smallcell carcinoma and the other two were squamous cell carcinomas. Here, we report the analysis of 90 cases of lung cancer using antibodies that recognize either the N or C terminus of CD43. In addition, we report the functional consequences of expressing CD43-targeted small-interfering RNA (siRNA) in the lung cancer cell line A549. Material and Methods Patient materialParaffin-embedded formalin-fixed tissues representing 90 cases of lung cancer and one mild case of lung silicosis were provided free-of-charge by the Gundersen Foundation BioBank (http://www.gundluth.org/biobank). Each case was sectioned, stained with hematoxylin and eosin and the histological diagnosis verified. All experimental procedures were

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Correlation between HIV‐1 seropositivity and prevalence of a γ‐secretase polymorphism in two distinct ethnic populations

Loo

Schijndel

Zweeden

et al. 2009

Journal of Medical Virology

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Susceptibility for human immunodeficiency virus type 1 (HIV-1) infection may be influenced by host genetics. Recent findings with a Wistar rat model raised the possibility that the gamma-secretase pathway may be associated with an individual's susceptibility to infection. A functional single-nucleotide polymorphism (SNP) in the gamma-secretase component APH1B (Phe217Leu; rs1047552) was therefore analyzed for association with HIV-1 infection. The SNP showed a tendency for association with HIV-1 infection in a Xhosa indigenous South African Bantu study (P = 0.087), and associated significantly in a Caucasian Dutch study (P = 0.049). Together, the results suggest a role for the gamma-secretase pathway in susceptibility to HIV-1 infection.

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Shedding and γ-secretase-mediated intramembrane proteolysis of the mucin-type molecule CD43

Cited by 39 publications

References 46 publications

Leukocyte marker CD43 promotes cell growth in co-operation with β-catenin in non-hematopoietic cancer cells

Leukocyte marker CD43 promotes cell growth in co-operation with β-catenin in non-hematopoietic cancer cells

CD43 in the nucleus and cytoplasm of lung cancer is a potential therapeutic target

Correlation between HIV‐1 seropositivity and prevalence of a γ‐secretase polymorphism in two distinct ethnic populations

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