Inhibition of JNK Promotes Differentiation of Epidermal Keratinocytes

Gazel, Alix; Banno, Tomohiro; Walsh, Rebecca; Blumenberg, Miroslav

doi:10.1074/jbc.m602712200

Cited by 78 publications

(89 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5). JNK activation seemed to be essential for the proliferation of stratified epithelial cells, because SP600125, a JNK inhibitor, drastically suppressed epidermal formation, which is consistent with a report that the JNK activity was essential for the development of stratified epidermis (17,58).…”

Section: Discussionsupporting

confidence: 77%

Ras Modifies Proliferation and Invasiveness of Cells Expressing Human Papillomavirus Oncoproteins

Yoshida

Kajitani

Satsuka

et al. 2008

J Virol

View full text Add to dashboard Cite

Infection by human papillomavirus (HPV) is a major risk factor for human cervical carcinoma. However, the HPV infection alone is not sufficient for cancer formation. Cervical carcinogenesis is considered a multistep process accompanied by genetic alterations of the cell. Ras is activated in approximately 20% of human cancers, and it is related to the metastatic conversion of tumor cells. We investigated how Ras activation was involved in the malignant conversion of HPV-infected lesions. The active form of H-ras was introduced into human primary keratinocytes expressing the HPV type 18 (HPV18) oncoproteins E6 and/or E7. We analyzed the keratinocytes' growth potentials and found that the activation of the Ras pathway induced senescence-like growth arrest. Senescence could be eliminated by high-risk E7 expression, suggesting that the pRb pathway was important for Ras-induced senescence. Then we analyzed the effect of Ras activation on epidermis development by using an organotypic "raft" culture and found that the E7 and H-ras coexpressions conferred invasive potential on the epidermis. This invasiveness resulted from the upregulation of MT1-MMP and MMP9 by H-ras and E7, respectively, in which the activation of the MEK/extracellular signal-regulated kinase pathway was involved. These results indicated that the activation of Ras or the related signal pathways promoted the malignant conversion of HPV-infected cells.

show abstract

Section: Discussionsupporting

confidence: 77%

Ras Modifies Proliferation and Invasiveness of Cells Expressing Human Papillomavirus Oncoproteins

Yoshida

Kajitani

Satsuka

et al. 2008

J Virol

View full text Add to dashboard Cite

show abstract

“…Our microarray studies suggest important epidermal function of the EFN/Eph system (Supplement 1). Specifically, we found that TNF␣ induces the expression of EFNA1 (25), and this induction exquisitely depends on the activation of the NFB tran-scription factor (26) but not on the MAPK kinases ERK, JNK, and p38 (27). In contrast, expression of EphA2 is induced by irradiation with UV light and by certain proinflammatory cytokines, e.g.…”

mentioning

confidence: 72%

“…In contrast, expression of EphA2 is induced by irradiation with UV light and by certain proinflammatory cytokines, e.g. Oncostatin M, which is dependent on the ERK and p38 signal transduction pathways (27)(28)(29)(30).…”

mentioning

confidence: 99%

Specific and Shared Targets of Ephrin A Signaling in Epidermal Keratinocytes

Walsh

Blumenberg

2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Both ephrins (EFNs) and their receptors (Ephs) are membrane-bound, restricting their interactions to the sites of direct cell-to-cell interfaces. They are widely expressed, often co-expressed, and regulate developmental processes, cell adhesion, motility, survival, proliferation, and differentiation. Both tumor suppressor and oncogene activities are ascribed to EFNs and Ephs in various contexts. A major conundrum regarding the EFN/Eph system concerns their large number and functional redundancy given the promiscuous cross-activation of ligands and receptors and the overlapping intracellular signaling pathways. To address this issue, we treated human epidermal keratinocytes with five EFNAs individually and defined the transcriptional responses in the cells. We found that a large set of genes is coregulated by all EFNAs. However, although the responses to EFNA3, EFNA4, and EFNA5 are identical, the responses to EFNA1 and EFNA2 are characteristic and distinctive. All EFNAs induce epidermal differentiation markers and suppress cell adhesion genes, especially integrins. Ontological analysis showed that all EFNAs induce cornification and keratin genes while suppressing wound healing-associated, signaling, receptor, and extracellular matrix-associated genes. Transcriptional targets of AP1 are selectively suppressed by EFNAs. EFNA1 and EFNA2, but not the EFNA3, EFNA4, EFNA5 cluster, regulate the members of the ubiquitin-associated proteolysis genes. EFNA1 specifically induces collagen production. Our results demonstrate that the EFN-Eph interactions in the epidermis, although promiscuous, are not redundant but specific. This suggests that different members of the EFN/Eph system have specific, clearly demarcated functions. Ephrins (EFNs)2 and ephrin receptors (Ephs) are cell membrane-bound proteins that act as bidirectional, reciprocal ligands between adjacent cells (1). EFNs are classified into two subfamilies, EFNA and EFNB, based on their glycosylphosphatidylinositol-anchored versus transmembrane structure, respectively. In parallel, their receptors, Ephs, are classified into the EphA or EphB family depending on the preference for EFNA or EFNB ligands, respectively (2). Direct cell-to-cell contact is usually necessary for signaling, and to be recognized as ligands, EFNs and Ephs have to be physically clustered. Gene knock-out studies have demonstrated that the EFN/Eph system plays a major role in patterning the vertebrate neural system (3, 4). In addition, EFN/Eph signaling systems function in vascular system assembly, carcinogenesis, and tumor progression (5-7).Ephs comprise the largest family of receptor tyrosine kinases with 14 members detected in humans (2). The intracellular domains of Ephs contain tyrosines that, when phosphorylated, serve as docking sites for signal transduction proteins, including SH2 and PTB domain proteins. Known signal transducers for Ephs are Src family kinases, the Jak/STAT3 pathway, Grb-2, Grb-10, Nck, PI3K, and Ras GTPase-activating protein (1,8). Ena/vasodilator-stimulated phosphoprotei...

show abstract

“…Epidermal keratinocytes have been the target of many studies because they respond to a rich variety of inflammatory and immunomodulating cytokines, hormones, vitamins, UV light, toxins and physical injury [16][17][18][19][20]. Transcriptional mechanisms that regulate epidermal differentiation and cornification have begun to yield their mysteries, and very exciting recent studies identified the genes specifically expressed in epidermal stem cells [21].…”

Section: Microarrays In Dermatology and Skin Biologymentioning

confidence: 99%

SKINOMICS: Transcriptional Profiling in Dermatology and Skin Biology

Blumenberg¹

2015

Encyclopedia of Metagenomics

Self Cite

View full text Add to dashboard Cite

Recent years witnessed the birth of bioinformatics technologies, which greatly advanced biological research. These 'omics' technologies address comprehensively the entire genome, transcriptome, proteome, microbiome etc. A large impetus in development of bioinformatics was the introduction of DNA microarrays for transcriptional profiling. Because of its accessibility, skin was among the first organs analyzed using DNA microarrays, and dermatology among the first medical disciplines to embrace the approach. Here, DNA microarray methodologies and their application in dermatology and skin biology are reviewed. The most studied disease has been, unsurprisingly, melanoma; markers of melanoma progression, metastatic potential and even melanoma markers in blood have been detected. The basal and squamous cell carcinomas have also been intensely studied. Psoriasis has been comprehensively explored using DNA microarrays, transcriptional changes correlated with genomic markers and several signaling pathways important in psoriasis have been identified. Atopic dermatitis, wound healing, keloids etc. have been analyzed using microarrays. Noninvasive skin sampling for microarray studies has been developed. Simultaneously, epidermal keratinocytes have been the subject of many skin biology studies because they respond to a rich variety of inflammatory and immunomodulating cytokines, hormones, vitamins, UV light, toxins and physical injury. The transcriptional changes occurring during epidermal differentiation and cornification have been identified and characterized. Recent studies identified the genes specifically expressed in human epidermal stem cells. As dermatology advances toward personalized medicine, microarrays and related 'omics' techniques will be directly applicable to the personalized dermatology practice of the future.

show abstract

Inhibition of JNK Promotes Differentiation of Epidermal Keratinocytes

Cited by 78 publications

References 70 publications

Ras Modifies Proliferation and Invasiveness of Cells Expressing Human Papillomavirus Oncoproteins

Ras Modifies Proliferation and Invasiveness of Cells Expressing Human Papillomavirus Oncoproteins

Specific and Shared Targets of Ephrin A Signaling in Epidermal Keratinocytes

SKINOMICS: Transcriptional Profiling in Dermatology and Skin Biology

Contact Info

Product

Resources

About