Methylosome Protein 50 and PKCδ/p38δ Protein Signaling Control Keratinocyte Proliferation via Opposing Effects on p21Cip1 Gene Expression

Abstract

Background: Keratinocytes cease proliferation during differentiation, and the mechanism that mediates these events is not well understood. Results: PRMT5/MEP50 control p21Cip1 promoter methylation to silence gene expression, and this is reversed by PKC␦/p38␦ signaling. Conclusion: PRMT5/MEP50 and PKC␦/p38␦ signaling produce opposing actions to control keratinocyte proliferation during differentiation. Significance: This study describes cross-talk between MAPK signaling and epigenetic mechanisms to control cell proliferation.

Expression of protein arginine methyltransferase‐5 in oral squamous cell carcinoma and its significance in epithelial‐to‐mesenchymal transition

“…In the nucleus, PRMT5 has been reported to promote cell proliferation and transformation via the switch/sucrose non‐fermenting (SWI/SNF) complex and nucleosome remodeling deacetylase (NuRD) chromatin‐remodeling complexes, in which it may methylate histones as well as transcription factors or regulators . In the cytoplasm, PRMT5 forms a 20S protein arginine methyltransferase complex termed the “methylosome”, which consists of spliceosomal snRNP Sm proteins, PRMT5, pICIn, and MEP50, to function as a master regulator of splicing …”

Protein kinases involved in epidermal barrier formation: The AKT family and other animals

“…MAPK kinases have long been implicated in keratinocyte differentiation; several MAP kinases, Mapk3, Mapk13 and Mapk14, are specifically expressed in the upper epidermis in the mouse on the mRNA level and knockouts of Mapk13 and murine models with modulation of MAPK signalling pathways display barrier defects, implicating these kinases in epidermal terminal differentiation . Additionally, the Erk1/2 effector c‐Jun is phosphorylated in the granular layer, in vitro and in vivo , suggesting that Erk1/2 is active in this region .…”

“…Induces p21 and epidermal terminal differentiation [49] MAPK14 ✓ Mitogen-activated protein kinase 14…”

“…[46] MAPK kinases have long been implicated in keratinocyte differentiation [47] ; several MAP kinases, Mapk3, Mapk13 and Mapk14, are specifically expressed in the upper epidermis in the mouse on the mRNA level [24] and knockouts of Mapk13 and murine models with modulation of MAPK signalling pathways display barrier defects, implicating these kinases in epidermal terminal differentiation. [48][49][50] Additionally, the Erk1/2 effector c-Jun is phosphorylated in the granular layer, in vitro and in vivo, suggesting that Erk1/2 is active in this region. [51][52][53] More recent work in human epidermis indicates a gradient of MAPK and ERK activation across the differentiating epidermis, correlating with the calcium gradient, [54,55] with ERK1/2 active in the nucleus of granular layer keratinocytes further suggesting a role for this signalling pathway in keratinocyte differentiation.…”

Studies on differentiation‐dependent expression and activity of distinct transglutaminases by specific substrate peptides using three‐dimensional reconstituted epidermis

“…The in vitro keratinocytes culture system have been successfully developed and used for many years to mimic normal skin formation . Though the current 3D reconstructed system, as a completed epidermis‐like structure, has been mainly used for tests or diagnoses in place of human epidermis, it is also appropriate for studies on keratinocyte differentiation . So far, the mechanisms of CE formation in terminal differentiation have been biochemically characterized regarding properties, components, and modification by TGs in the skin epidermis and ordinary 2D cultured cells .…”