Desmoglein 1–dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis

Getsios, Spiro; Simpson, Cory L.; Kojima, Shin Ichiro; Harmon, Robert M.; Sheu, Linda J.; Dusek, Rachel L.; Cornwell, Mona; Green, Kathleen J.

doi:10.1083/jcb.200809044

Cited by 197 publications

(280 citation statements)

References 66 publications

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“…A previous study reported that another isoform of Dsg, Dsg1, is expressed in suprabasal differentiated keratinocytes and is required for suppressing EGFR-extracellular signalregulated kinase (Erk) 1/2 signaling to allow for normal differentiation. 13 However, cell proliferation was not measured in this study. As we had observed that EGFR signaling promotes proliferation in Dsc2-deficient colonic epithelial cells, 7 we assessed whether EGFR signaling was altered in SK-CO15 cells lacking Dsg2.…”

Section: Egfr Signaling Is Diminished In Cells Lacking Dsg2mentioning

confidence: 90%

Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling

隆太¹

2014

Journal of Japan Society of Immunology & Allergology in Oto

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Desmosomal cadherins mediate cell-cell adhesion in epithelial tissues and have been known to be altered in cancer. We have previously shown that one of the two intestinal epithelial desmosomal cadherins, desmocollin-2 (Dsc2) loss promotes colonic epithelial carcinoma cell proliferation and tumor formation. In this study we show that loss of the other intestinal desmosomal cadherin, desmoglein-2 (Dsg2) that pairs with Dsc2, results in decreased epithelial cell proliferation and suppressed xenograft tumor growth in mice. Dsg2-deficient cells demonstrated a compensatory increase in Dsc2 expression, and small interfering RNA-mediated loss of Dsc2 restored proliferation in Dsg2-deficient cells. Dsg2 downregulation inhibited epidermal growth factor receptor (EGFR) signaling and cell proliferation through altered phosphorylation of EGFR and downstream extracellular signal-regulated kinase activation in parallel with inhibited EGFR receptor internalization. Additionally, we demonstrated a central role of Dsc2 in controlling EGFR signaling and cell proliferation in intestinal epithelial cells. Consistent with these findings, analyses of human colon cancers demonstrated increased Dsg2 protein expression. Taken together, these data demonstrate that partner desmosomal cadherins Dsg2 and Dsc2 play opposing roles in controlling colonic carcinoma cell proliferation through differential effects on EGFR signaling.

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Section: Egfr Signaling Is Diminished In Cells Lacking Dsg2mentioning

confidence: 90%

Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling

隆太¹

2014

Journal of Japan Society of Immunology & Allergology in Oto

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“…Human cervical cancer HeLa cells and human keratinocyte line HaCaT cells were maintained in DMEM (Gibco®; Invitrogen) with 10% heat-inactivated fetal bovine serum. Human skin equivalents were generated by the Skin Disease Research Center (SDRC) at Northwestern University (NU) and used when they were fully differentiated as intact skin (42). Studies were also performed with EpiDerm skin model samples (MatTek), grown in medium provided by MatTek.…”

Section: Methodsmentioning

confidence: 99%

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

368

288

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Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNANCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are >100-fold more potent and suppress longer than siRNA delivered with commercial lipid agents in cultured keratinocytes. Topical delivery of 1.5 uM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equivalents is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clinical or histological evidence of toxicity. No cytokine activation in mouse blood or tissue samples is observed, and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.T he recent development of small molecule inhibitors and antibodies that target components of signaling pathways has revolutionized the treatment of cancers, inflammatory diseases, and genetic disorders, including those that largely manifest in skin (1-3). These protein-based therapeutics, however, are costly, have limited targeting ability, and, when delivered through traditional intravenous or gastrointestinal routes, can lead to systemic toxicity (4, 5). Topical delivery is particularly attractive for the therapy of skin disorders. However, proteins larger than a few hundred daltons cannot easily enter the skin, and high concentrations of proteins must be applied for a cutaneous effect (6). An alternative to protein-based pathway inhibition involves the blocking and/or degradation of precursor mRNA before translation into protein. Gene silencing leads to down-regulation of protein expression and functions with greater specificity than inhibitors of protein function (7). In fact, targeted gene suppression by antisense DNA and siRNA has shown promising preclinical results, and/or is currently in clinical trials for a variety of diseases, including many forms of cancer (e.g., melanoma, neuroblastoma, and pancreatic adenocarcinoma), genetic disorders, and macular degeneration (8). For gene su...

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“…Raft cultures of HEKs were produced by the Northwestern University Skin Disease Research Center's keratinocyte core facility. Briefly, HEKs were grown to confluence in E-medium [DMEM/F12, 5% (vol/vol) FBS] with EGF (5 ng/mL) and switched to an air-medium interface for 3, 7, and 12 d (23). The raft cultures of hTCEpi cells were derived as previously described (33).…”

Section: Methodsmentioning

confidence: 99%

“…2A). To investigate this FIH-1 attenuation in HEK differentiation and increase in proliferation in a more physiologically relevant manner, we used a three-dimensional organotypic raft model of human epidermis (23). FIH-1 was detected in the nucleus and cytoplasm of cells in all but the uppermost cornified layer of raft cultures generated from FIH-1-transduced HEKs ( Fig.…”

Section: Fih-1 Expression Is Elevated In Conditions Of Abnormal Epithmentioning

confidence: 99%

microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation

Han¹,

Kaplan²,

Hamanaka

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

102

119

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Notch plays a critical role in the transition from proliferation to differentiation in the epidermis and corneal epithelium. Furthermore, aberrant Notch signaling is a feature of diseases like psoriasis, eczema, nonmelanoma skin cancer, and melanoma where differentiation and proliferation are impaired. Whereas much is known about the downstream events following Notch signaling, factors responsible for negatively regulating Notch receptor signaling after ligand activation are incompletely understood. Notch can undergo hydroxylation by factor-inhibiting hypoxia-inducible factor 1 (FIH-1); however, the biological significance of this phenomenon is unclear. Here we show that FIH-1 expression is upregulated in diseased epidermis and corneal epithelium. Elevating FIH-1 levels in primary human epidermal keratinocytes (HEKs) and human corneal epithelial keratinocytes (HCEKs) impairs differentiation in submerged cultures and in a "three-dimensional" organotypic raft model of human epidermis, in part, via a coordinate decrease in Notch signaling. Knockdown of FIH-1 enhances keratinocyte differentiation. Loss of FIH-1 in vivo increased Notch activity in the limbal epithelium, resulting in a more differentiated phenotype. microRNA-31 (miR-31) is an endogenous negative regulator of FIH-1 expression that results in keratinocyte differentiation, mediated by Notch activation. Ectopically expressing miR-31 in an undifferentiated corneal epithelial cell line promotes differentiation and recapitulates a corneal epithelium in a three-dimensional raft culture model. Our results define a previously unknown mechanism for keratinocyte fate decisions where Notch signaling potential is, in part, controlled through a miR-31/FIH-1 nexus.

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Desmoglein 1–dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis

Cited by 197 publications

References 66 publications

Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling

Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation

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