Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3K pathway

The MAL gene encodes a 17-kDa protein containing four putative transmembrane segments whose expression is restricted to human T cells, polarized epithelial cells and myelin-forming cells. The MAL protein has two unusual biochemical features. First, it has lipid-like properties that qualify it as a member of the group of proteolipid proteins. Second, it partitions selectively into detergent-insoluble membranes, which are known to be enriched in condensed cell membranes, consistent with MAL being distributed in highly ordered membranes in the cell. Since its original description more than thirty years ago, a large body of evidence has accumulated supporting a role of MAL in specialized membranes in all the cell types in which it is expressed. Here, we review the structure, expression and biochemical characteristics of MAL, and discuss the association of MAL with raft membranes and the function of MAL in polarized epithelial cells, T lymphocytes, and myelin-forming cells. The evidence that MAL is a putative receptor of the epsilon toxin of Clostridium perfringens, the expression of MAL in lymphomas, the hypermethylation of the MAL gene and subsequent loss of MAL expression in carcinomas are also presented. We propose a model of MAL as the organizer of specialized condensed membranes to make them functional, discuss the role of MAL as a tumor suppressor in carcinomas, consider its potential use as a cancer biomarker, and summarize the directions for future research.

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Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells

Nature Communications ◽

10.1038/s41467-021-23957-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Patrick D. Rädler ◽

Barbara L. Wehde ◽

Aleata A. Triplett ◽

Hridaya Shrestha ◽

Jonathan H. Shepherd ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Epithelial Cells ◽

Triple Negative ◽

Molecular Subtype ◽

Ras Signaling ◽

Preneoplastic Lesions ◽

Independent Manner ◽

Oncogenic Ras ◽

Luminal Epithelial Cells

AbstractClaudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.

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Delivery of Na+,K(+)-ATPase in polarized epithelial cells

Science ◽

10.1126/science.8386394 ◽

1993 ◽

Vol 260 (5107) ◽

pp. 550-552 ◽

Cited By ~ 42

Author(s):

C Zurzolo ◽

E Rodriguez-Boulan

Keyword(s):

Epithelial Cells ◽

Polarized Epithelial Cells

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The Role of the Cytoskeleton and Myosin-Vc in the Targeting of KCa3.1 to the Basolateral Membrane of Polarized Epithelial Cells

Frontiers in Physiology ◽

10.3389/fphys.2016.00639 ◽

2017 ◽

Vol 7 ◽

Cited By ~ 2

Author(s):

Rachel E. Farquhar ◽

Ely Rodrigues ◽

Kirk L. Hamilton

Keyword(s):

Epithelial Cells ◽

Basolateral Membrane ◽

Polarized Epithelial Cells

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Treponema denticola Induces Epithelial Barrier Dysfunction in Polarized Epithelial Cells

The Bulletin of Tokyo Dental College ◽

10.2209/tdcpublication.2017-0052 ◽

2018 ◽

Vol 59 (4) ◽

pp. 265-275 ◽

Cited By ~ 1

Author(s):

Yuichiro Kikuchi ◽

Ryuta Kimizuka ◽

Tetsuo Kato ◽

Katsuji Okuda ◽

Eitoyo Kokubu ◽

...

Keyword(s):

Epithelial Cells ◽

Epithelial Barrier ◽

Treponema Denticola ◽

Barrier Dysfunction ◽

Polarized Epithelial Cells ◽

Epithelial Barrier Dysfunction

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TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2

eLife ◽

10.7554/elife.23242 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 7

Author(s):

Amy T Ku ◽

Timothy M Shaver ◽

Ajay S Rao ◽

Jeffrey M Howard ◽

Christine N Rodriguez ◽

...

Keyword(s):

Tumor Growth ◽

Embryonic Stem ◽

Xenograft Model ◽

Transcriptome Profiling ◽

Loss Of Function ◽

Skin Tumorigenesis ◽

Oncogenic Ras ◽

Downstream Effector ◽

Skin Squamous Cell Carcinoma ◽

Chemically Induced

The transcription factor TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with β-catenin. Through transcriptome profiling and combined gain- and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity.

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