Cyclin D1 localizes in the cytoplasm of keratinocytes during skin differentiation and regulates cell–matrix adhesion

Fernández-Hernández, Rita; Rafel, Marta; Fusté, Noel P.; Aguayo, Rafael; Casanova, Josep Manel; Egea, Joaquim; Ferrezuelo, Francisco; Garí, Eloi

doi:10.4161/cc.25590

Cited by 24 publications

(23 citation statements)

References 32 publications

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“…ChIP-seq analysis of DLX3 and H3K4me3 DNA binding domains identified DLX3-bound promoter regions of genes involved in cell cycle regulation during differentiation, such as Ccnd1, Ccne1; 41, 42 and epidermal structure, such as Clic4, Dsp, Evpl, Fabp5, 43, 44, 45, 46 and transcription factors such as Grhl3, Klf4, Msx2 and Notch1 47, 48, 49, 50 (Figure 8). Together with the transcriptomic analysis, the ChIP-seq analysis of DLX3 and H4K4m3 binding supports a potential DLX3-dependent transcriptional regulation of these genes during epidermal differentiation.…”

Section: Resultsmentioning

confidence: 99%

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

et al. 2017

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Epidermal homeostasis relies on a well-defined transcriptional control of keratinocyte proliferation and differentiation, which is critical to prevent skin diseases such as atopic dermatitis, psoriasis or cancer. We have recently shown that the homeobox transcription factor DLX3 and the tumor suppressor p53 co-regulate cell cycle-related signaling and that this mechanism is functionally involved in cutaneous squamous cell carcinoma development. Here we show that DLX3 expression and its downstream signaling depend on protein kinase C α (PKCα) activity in skin. We found that following 12-O-tetradecanoyl-phorbol-13-acetate (TPA) topical treatment, DLX3 expression is significantly upregulated in the epidermis and keratinocytes from mice overexpressing PKCα by transgenic targeting (K5-PKCα), resulting in cell cycle block and terminal differentiation. Epidermis lacking DLX3 (DLX3cKO), which is linked to the development of a DLX3-dependent epidermal hyperplasia with hyperkeratosis and dermal leukocyte recruitment, displays enhanced PKCα activation, suggesting a feedback regulation of DLX3 and PKCα. Of particular significance, transcriptional activation of epidermal barrier, antimicrobial peptide and cytokine genes is significantly increased in DLX3cKO skin and further increased by TPA-dependent PKC activation. Furthermore, when inhibiting PKC activity, we show that epidermal thickness, keratinocyte proliferation and inflammatory cell infiltration are reduced and the PKC-DLX3-dependent gene expression signature is normalized. Independently of PKC, DLX3 expression specifically modulates regulatory networks such as Wnt signaling, phosphatase activity and cell adhesion. Chromatin immunoprecipitation sequencing analysis of primary suprabasal keratinocytes showed binding of DLX3 to the proximal promoter regions of genes associated with cell cycle regulation, and of structural proteins and transcription factors involved in epidermal differentiation. These results indicate that Dlx3 potentially regulates a set of crucial genes necessary during the epidermal differentiation process. Altogether, we demonstrate the existence of a robust DLX3-PKCα signaling pathway in keratinocytes that is crucial to epidermal differentiation control and cutaneous homeostasis.

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Section: Resultsmentioning

confidence: 99%

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

et al. 2017

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“…In breast cancer cells, cyclin D1 interacts with cytoskeletal proteins and controls migration [12]. In keratinocytes, cytoplasmic cyclin D1 regulates cell-matrix adhesion [13]. We assessed the capacity of GFP- and D1-GFP-expressing clones to adhere to fibronectin or HS-5 stromal cells after their staining with calcein-AM.…”

Section: Resultsmentioning

confidence: 99%

Cyclin D1 unbalances the redox status controlling cell adhesion, migration, and drug resistance in myeloma cells

et al. 2016

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The interactions of multiple myeloma (MM) cells with their microenvironment are crucial for pathogenesis. MM cells could interact differentially with their microenvironment depending on the type of cyclin D they express. We established several clones that constitutively express cyclin D1 from the parental RPMI8226 MM cell line and analyzed the impact of cyclin D1 expression on cell behavior. We performed a gene expression profiling study on cyclin D1-expressing vs. control cells and validated the results by semi-quantitative RT-PCR. The expression of cyclin D1 altered the transcription of genes that control adhesion and migration. We confirmed that cyclin D1 increases cell adhesion to stromal cells and fibronectin, stabilizes F-actin fibers, and enhances chemotaxis and inflammatory chemokine secretion. Both control and cyclin D1-expressing cells were more resistant to acute carfilzomib treatment when cultured on stromal cells than in suspension. However, this resistance was specifically reduced in cyclin D1-expressing cells after pomalidomide pre-treatment that modifies tumor cell/microenvironment interactions. Transcriptomic analysis revealed that cyclin D1 expression was also associated with changes in the expression of genes controlling metabolism. We also found that cyclin D1 expression disrupted the redox balance by producing reactive oxygen species. The resulting oxidative stress activated the p44/42 mitogen-activated protein kinase (or ERK1/2) signaling pathway, increased cell adhesion to fibronectin or stromal cells, and controlled drug sensitivity.Our results have uncovered a new function for cyclin D1 in the control of redox metabolism and interactions of cyclin D1-expressing MM cells with their bone marrow microenvironment.

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“…Ectopic overexpression of cyclin D1 increases β1 integrin recycling upon differentiation, as demonstrated by a pronounced loss of membrane-bound β1 integrin, and leads to reduced keratinocyte adhesion to the extracellular matrix 131 . Cell migration and the actin cytoskeleton are also modulated by cyclins and CDKs at different levels 132 .…”

Section: Regulation Of Cell Migrationmentioning

confidence: 99%

Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases

Hydbring

Malumbres

Siciński

2016

Nat Rev Mol Cell Biol

418

365

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The role of cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), as core components of the machinery that drives cell cycle progression is well established. Increasing evidence indicates that mammalian cyclins and CDKs also carry out important roles in other cellular processes such as transcription, DNA damage repair, the control of cell death, differentiation, the immune response and metabolism. Some of these non-canonical functions are performed by cyclins or by CDKs, independent of their respective cell cycle partners, suggesting a substantial divergence in the function of these proteins during evolution.

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Cyclin D1 localizes in the cytoplasm of keratinocytes during skin differentiation and regulates cell–matrix adhesion

Cited by 24 publications

References 32 publications

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

Cyclin D1 unbalances the redox status controlling cell adhesion, migration, and drug resistance in myeloma cells

Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases

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