MUC1 Oncoprotein Blocks Glycogen Synthase Kinase 3β–Mediated Phosphorylation and Degradation of β-Catenin

Huang, Lei; Chen, Dongshu; Liu, Derek; Li, Yin; Kharbanda, Surender; Küfe, Donald

doi:10.1158/0008-5472.can-05-2474

Cited by 212 publications

(325 citation statements)

References 48 publications

(77 reference statements)

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“…Estimates indicate that ~800,000 of the 1.4 million tumors diagnosed annually in the US overexpress MUC1. Recent studies have demonstrated that the overexpression of MUC1 induces transformation (6) and that the oncogenic sequences reside in the MUC1 C-terminal subunit (20,44). However, no information is available regarding the origin of the MUC1-C extracellular and cytoplasmic domains.…”

Section: Discussionmentioning

confidence: 99%

“…The MUC1-CD binds to ß-catenin and increases ß-catenin levels by blocking its degradation (20). Moreover, MUC1-CD is sufficient to induce transformation by a mechanism that is at least in part dependent on the interaction with ß-catenin (20).…”

Section: Discussionmentioning

confidence: 99%

“…MUC1-C is targeted to the nucleus (6,10,(16)(17)(18) and mitochondria (8,19). In addition, MUC1-C stabilizes the Wnt effector, ß-catenin, through direct binding of the MUC1-C cytoplasmic domain (MUC1-CD) and the ß-catenin Arm repeats (20). Overexpression of MUC1-CD is sufficient for the induction of transformation and the interaction between MUC1-CD and ß-catenin is in part responsible for this response (20).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, MUC1-C stabilizes the Wnt effector, ß-catenin, through direct binding of the MUC1-C cytoplasmic domain (MUC1-CD) and the ß-catenin Arm repeats (20). Overexpression of MUC1-CD is sufficient for the induction of transformation and the interaction between MUC1-CD and ß-catenin is in part responsible for this response (20). Other studies have demonstrated that MUC1-CD functions as a substrate for glycogen synthase 3ß (21), c-Src (22), protein kinase Cδ (23) and c-Abl (12).…”

Section: Introductionmentioning

confidence: 99%

“…These findings have indicated that, in contrast to the N-terminal mucin-type ectodomain, MUC1-C transduces signals from the cell membrane to the interior of the cell that confer growth and survival responses. The available evidence indicates that MUC1-CD functions like a chaperone that holds client proteins in configurations that dictate activity (10,18,20).…”

Section: Introductionmentioning

confidence: 99%

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Evolution of the human MUC1 oncoprotein

Duraisamy¹,

Kufe²,

Ramasamy³

et al. 2007

Int J Oncol

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Abstract. The mucin (MUC) family consists of secreted and membrane-bound forms. The transmembrane mucin 1 (MUC1) is a heterodimer that is aberrantly overexpressed by diverse human carcinomas and certain hematologic malignancies. The MUC1 N-terminal (MUC1-N) and C-terminal (MUC1-C) subunits are generated by autocleavage within a SEA domain. The MUC1 cytoplasmic domain (MUC1-CD) located downstream of the SEA domain is sufficient for the induction of anchorage-independent growth and tumorigenicity; however, no information is available regarding the origin of these transforming sequences. Previous work demonstrated that, except for the SEA domain, MUC1 has no sequence homology with other membrane-bound mucins. The present results demonstrate that MUC1-CD evolved from repeat regions in the MUC5B secreted mucin. We also show that MUC1 sequences upstream to the SEA domain emerged from MUC5B. These findings indicate that both the MUC1-N and MUC1-C subunits evolved from secreted gel-forming mucins and that the MUC1-CD oncogenic function emerged by diversification after evolution from MUC5B.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Evolution of the human MUC1 oncoprotein

Duraisamy¹,

Kufe²,

Ramasamy³

et al. 2007

Int J Oncol

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The MUC1 oncoprotein as a functional target: Immunotoxin binding to α/β junction mediates cell killing

Rubinstein

Karmely

Pichinuk

et al. 2008

Intl Journal of Cancer

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MUC1, a heavily glycosylated mucin, has generated considerable interest as a target for tumor killing because of its overexpression in malignancies. Full-length MUC1 (MUC1/TM) is proteolytically cleaved after synthesis generating a and b subunits, which specifically bind in a noncovalent interaction. Although the b chain remains on the cell surface, the a chain binds in an on-and-off interaction. Most anti-MUC1 antibodies (Abs) described to date recognize epitopes within the highly immunogenic a-chain tandem repeat. Because the a-chain is shed, such Abs are sequestered and fail to reach MUC1-expressing cells. Immunizing with cDNA encoding MUC1/TM and the spliced MUC1/X isoform from which the tandem repeat has been deleted yielded antibodies to the MUC1 a/b junction. Pseudomonas toxin PE38 linked to polyclonal anti-MUC1 a/b junction Abs both bound and killed MUC1-positive malignant cells. Monoclonal DMC209 binds the MUC1 a/b junction in both MUC1/X and MUC1/TM. When injected into SCID mice xenotransplanted with human breast cancer MDA-MB-231, monoclonal DMC209 showed significant in vivo tumorsuppressive activity. The MUC1/X a/b junction presents a biologically-significant target in MUC1-expressing malignancies because (i) antibodies directed against cell-bound a/b junction epitopes reach the intended cellular target, (ii) antibodies to junction epitope are internalized into cells, (iii) anti a/b junction antibodies can effectively kill high MUC1-expressing cancer cells as antibody-toxin conjugates and (iv) antibodies targeting the MUC1 cell-bound a/b junction results in tumor suppression in vivo. Our results indicate that cell-bound MUC1 a/b junction, unlike shed alpha chain, represents a highly effective moiety for targeting and killing MUC1-expressing malignancies. ' 2008 Wiley-Liss, Inc.Key words: MUC1; a/b; junction; oncogene; cancer cell killing; target-specific therapy Mucins are heavily glycosylated proteins found on both normal and malignantly transformed epithelial cells and preferentially expressed by a variety of adenocarcinomas, including breast, prostate, ovarian and pancreatic carcinomas, as well as on the malignant plasma cells of multiple myeloma. 1-5 Because of their presence on the cell surface, mucins play an important role in cell adhesion and matrix formation. 6 In addition to cell-to-cell functions, the transmembrane mucin molecule undergoes phosphorylation on its intracellular cytoplasmic tail, 7 thereby initiating intracellular transduction cascades that influence cellular proliferation and survival. 8-14 MUC1 mucin, because of its high expression on a number of different human tumor types, is widely recognized as a potentially important target for targeting human epithelial cancer cells. [15][16][17][18][19][20] The most intensively studied MUC1 protein is a type I transmembrane protein (MUC1/TM) composed of extracellular, transmembrane and cytoplasmic domains. 5,21 MUC1/TM is proteolytically cleaved soon after its synthesis, 22-26 generating two subunits, a and b, which specifically reco...

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Inhibition of MUC1‐C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma

Gongsun

Zhao

Jiang

et al. 2018

Journal Cellular Physiology

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Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive tumors worldwide. The Mucin 1 (MUC1) heterodimeric protein has been confirmed that is overexpressed in ESCC and induced adverse outcomes. However, the detailed mechanism(s) remained challenging. So, we investigated the relationship between MUC1‐C and metabolism in ESCC cells. In the results, TP53‐induced glycolysis and apoptosis regulator (TIGAR) was overexpressed and correlative with MUC1‐C positively in ESCC tissue. Targeting MUC1‐C inhibits AKT–mTORC–S6K1 signaling and blocks TIGAR translation. We found that the inhibitory effect of GO‐203 on TIGAR was mediated by inhibition of AKT–mTOR–S6K1 pathway. The findings also demonstrated that the suppressive effect of GO‐203 on TIGAR is related to the decrease of glutathione level, the increase of reactive oxygen species and the loss of mitochondrial transmembrane membrane potential. In xenograft tissues, GO‐203 inhibited the growth of ESCC cells and lead to the low expression of transmembrane C‐terminal subunit (MUC1‐C) and TIGAR. This evidence supports the contention that MUC1‐C is significant for metabolism in ESCC and indicated that MUC1‐C is a potential target for the treatment of ESCC.

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MUC1 Oncoprotein Blocks Glycogen Synthase Kinase 3β–Mediated Phosphorylation and Degradation of β-Catenin

Cited by 212 publications

References 48 publications

Evolution of the human MUC1 oncoprotein

Evolution of the human MUC1 oncoprotein

The MUC1 oncoprotein as a functional target: Immunotoxin binding to α/β junction mediates cell killing

Inhibition of MUC1‐C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma

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