Human DF3/MUC1 carcinoma-associated protein functions as an oncogene

Li, Yongqing; Liu, Derek; Chen, Dongshu; Kharbanda, Surender; Küfe, Donald

doi:10.1038/sj.onc.1206732

Cited by 185 publications

(175 citation statements)

References 18 publications

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“…Other studies have shown that phosphorylation of MUC1 by the epidermal growth factor receptor (25), c-Src (26), and protein kinase C␦ (PKC␦) (27) induces binding of MUC1 and ␤-catenin. These findings indicate that MUC1 functions by integrating signals from growth factor receptors, which also activate PI3K/Akt (1) and the Wnt pathway.Overexpression of MUC1 is sufficient to induce the transformation of rat 3Y1 fibroblasts (20). The present studies demonstrated that expression of MUC1 in 3Y1 cells is associated with the activation of the PI3K/Akt pathway.…”

supporting

confidence: 62%

“…Overexpression of MUC1 is sufficient to induce the transformation of rat 3Y1 fibroblasts (20). The present studies demonstrated that expression of MUC1 in 3Y1 cells is associated with the activation of the PI3K/Akt pathway.…”

supporting

confidence: 62%

“…Cell Culture-Rat 3Y1 fibroblasts stably expressing the empty vector or full-length MUC1 (20) were cultured in Dulbecco's modified Eagle's medium containing 10% heat-inactivated fetal calf serum, 100 units/ml penicillin, 100 g/ml streptomycin, and 2 mM L-glutamine. Two independently selected clones (A and B) were used for both 3Y1/vector and 3Y1/MUC1 cells (20).…”

Section: Methodsmentioning

confidence: 99%

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The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Raina

Kharbanda

Küfe

2004

Journal of Biological Chemistry

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154

144

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The MUC1 transmembrane glycoprotein is overexpressed by most human carcinomas. Overexpression of MUC1 confers transformation; however, the signaling pathways activated by this oncoprotein are largely unknown. The present studies demonstrated that MUC1-induced transformation of 3Y1 fibroblasts is associated with increased levels of phospho-Akt and phospho-Bad. The finding that LY294002 blocks MUC1-mediated increases in phospho-Akt and phospho-Bad supports the involvement of phosphoinositide 3-kinase (PI3K) as an upstream effector of this response. We also show that MUC1 increases the expression of the anti-apoptotic Bcl-x L protein (but not Bcl-2) by a PI3K-independent mechanism. In concert with these results, MUC1 attenuated (i) the loss of mitochondrial transmembrane potential, (ii) mitochondrial cytochrome c release, (iii) activation of caspase-9, and (iv) induction of apoptosis by the antimetabolite, 1-␤-D-arabinofuranosylcytosine. Similar results were obtained with the anti-cancer agent, gemcitabine. These findings indicate that expression of MUC1 in 3Y1 cells activates the anti-apoptotic PI3K/Akt and Bcl-x L pathways.The phosphoinositide 3-kinase (PI3K) 1 /Akt signaling pathway is of importance in promoting cell survival. PI3K, which consists of a p85 regulatory subunit and a p110 catalytic subunit, phosphorylates phosphatidylinositols (PIs) at their 3-position and thereby converts PI(4,5)P 2 to PI(3,4,5)P 3 (1). The serine-threonine Akt/PKB kinase and the phosphoinositide-dependent kinase 1 (PDK1) localize at cell membrane sites by direct binding to PI(3,4,5)P 3 through their pleckstrin-homology domains (2, 3). Phosphorylation of Akt by PDK1 stimulates Akt activity (4). In turn, Akt phosphorylates and inactivates the Forkhead-related transcription factor 1 by retaining it in the cytosol in a complex with 14-3-3 proteins. Similarly, Akt phosphorylates Bad, induces binding of Bad to 14-3-3 proteins, and prevents Bad from interacting with the anti-apoptotic Bcl-2 and Bcl-x L proteins (5). The activity of the pro-death caspase-9 protease is inhibited by Akt-mediated phosphorylation (6). Akt can also confer cell survival by indirect regulation of NF-B through I B kinase (7, 8) and of p53 through Mdm2 (9, 10). These findings, and the demonstration that PI3K/Akt signaling is dysregulated in human malignancies, have provided support for the significance of this pathway in conferring tumor cell survival (11).The human DF3/MUC1 transmembrane glycoprotein is expressed on the apical borders of normal secretory epithelial cells (12). The MUC1 protein is synthesized as a single polypeptide that is cleaved in the endoplasmic reticulum into N-terminal and C-terminal subunits, which then reside as heterodimers at the apical cell surface (13,14). The large (Ͼ250 kDa) N-terminal ectodomain (N-ter) contains variable numbers of 20-amino acid tandem repeats that are heavily glycosylated (15, 16). The smaller (ϳ25 kDa) C-terminal subunit (C-ter) consists of an extracellular domain of 58 amino acids, a 28-amino acid transmembrane...

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supporting

confidence: 62%

supporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Raina

Kharbanda

Küfe

2004

Journal of Biological Chemistry

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154

144

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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 C-terminal subunit (MUC1-C) consists of a 58 amino acid extracellular domain, a 28 amino acid transmembrane domain and a 72 amino acid cytoplasmic tail (15). 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).…”

Section: Introductionmentioning

confidence: 99%

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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Downregulation of MUC1 expression and its recognition by CD8⁺ T cells on the surface of malignant pleural mesothelioma cells treated with HDACi

et al. 2012

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Research into new treatments against malignant pleural mesothelioma (MPM) is of great interest, as this aggressive cancer is often resistant to conventional therapies. One potential strategy is the use of epigenetic drugs, such as 5-aza-2 0 -deoxycytidine (5-azaCdR), a DNAhypomethylating drug, and valproate (VPA), a histone deacetylase inhibitor (HDACi). Indeed, these drugs not only trigger MPM cell death, but also induce the expression of cancer testis antigens recognized by CD8 1 T cells, such as New York-esophageal cancer-1 (NY-ESO-1). The objective of this study was to assess effects of these drugs on the expression and recognition by CD8 1 T cells of Mucin1 (MUC1), a tumor-associated antigen that is overexpressed by MPM.MPM tumor cell lines were treated with epigenetic drugs, alone or in combination. MUC1 expression by MPM cells, and its recognition by a MUC1-specific CD8 1 T-cell clone, was downregulated by HDACi when used alone or in combination with 5-azaCdR. This effect was not due to a blocking of the HLA class I presentation pathway in treated MPM cells, as NY-ESO-1 induced by 5-azaCdR alone, or with VPA, was recognized by a NY-ESO-1-specific T-cell clone. This study suggests that the choice of tumor antigens could be critical for strategies combining epigenetic drugs with immunotherapy.

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Human DF3/MUC1 carcinoma-associated protein functions as an oncogene

Cited by 185 publications

References 18 publications

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Evolution of the human MUC1 oncoprotein

Downregulation of MUC1 expression and its recognition by CD8⁺ T cells on the surface of malignant pleural mesothelioma cells treated with HDACi

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Human DF3/MUC1 carcinoma-associated protein functions as an oncogene

Cited by 185 publications

References 18 publications

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts

Evolution of the human MUC1 oncoprotein

Downregulation of MUC1 expression and its recognition by CD8+ T cells on the surface of malignant pleural mesothelioma cells treated with HDACi

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Product

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Downregulation of MUC1 expression and its recognition by CD8⁺ T cells on the surface of malignant pleural mesothelioma cells treated with HDACi