230 Psoriatic epidermis is associated with upregulation of CDK2 and inhibition of CDK4 activity

Abstract

Cyclin-dependent kinases (CDKs) are involved in regulation of cell cycle and passage through the G1 restriction point relies on CDK4/6 and their association with cyclin D1 (CycD1) whereas entry into S phase requires CDK2 and its association with cyclin E (CycE). The levels of cyclin partners, their phosphorylation status, and the abundance of inhibitors of CDK (CDKI) regulate CDK activity. CKIs may be implicated in signaling pathways that are involved in psoriasis pathogenesis and regulation of G1 and S phases by CDKs is relevant for inflammatory skin diseases that are associated with proliferative cell disorders. To monitor CDK2 and CDK4 activity in human epidermis we used CDKACT fluorescent biosensors that undergo fluorescence enhancement upon phosphorylation by CDKs. By using confocal and Western blot analysis, we evaluated the expression of CDK4/2, Cyc D1/E and CDKI such as p16 INK4A (p16), p21 Cip1 (p21) and p27 Kip1 (p27). A cohort of 24 patients was asked to participate in the study. Punch biopsies were taken from a chronic plaque and from non-lesional skin of the same patient. CDK4 and its CycD1 partner were overexpressed in psoriatic epidermis. Epidermal QPCR analysis showed that the increased CDK4 expression was not due to enhanced transcription. Compared to normal skin there was no increase in CDK4/ CyclinD1 activity. CDK2 and CycE were overexpressed in psoriatic epidermis and this overexpression was correlated with an increase in CDK2-CycE activity. Increased CDK2 expression was not related to enhanced transcription. There was an increased expression of p16 and p21 whereas p27 was decreased in psoriatic epidermis. We have have shown that epidermal CDK2 activity was greatly increased in psoriatic epidermis while CDK4 activity was completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control that may be mediated by a dysregulation of CDKI expresion in psoriatic epidermis.

Lysophosphatidic Acid Mediates Imiquimod-Induced Psoriasis-like Symptoms by Promoting Keratinocyte Proliferation through LPAR1/ROCK2/PI3K/AKT Signaling Pathway

“…Consistently, the expression of p27 Kip1 , a negative CDK2 regulator [ 44 ], decreased in HaCaT cells by LPA treatment and was restored by ki16425 treatment ( Figure 4 ). In agreement with this result, p27 Kip1 expression reduces in psoriatic epidermis of psoriasis patients [ 45 ].…”

Psoriatic epidermis expresses high level of inflammatory mediators and the CDK2/4 cyclin‐dependent kinases are involved in the regulation of cell‐cycle progression in epidermal cells

“…1 Interestingly, this study reveals that, in an insurance-based French cohort of 14 147 adult patients with psoriasis, the discontinuation rate at 1 year was significantly higher for apremilast than for MTX in monotherapy (69% vs. 58%), even after adjusting for age, sex, comorbidities, psoriatic arthritis and previous therapies. 1 The present study provides a real-world arsenal of data to dermatologists considering their approach to treating adult 'biologic-naive' patients with psoriasis, demonstrating that patients are more likely to continue to use MTX than apremilast. However, pure head-to-head comparison data are not the only consideration when deciding between these two medications; absolute contraindications play a pivotal role.…”

“…Henri et al . present new and exciting results regarding the regulation of CDK2 and CDK4 in psoriatic skin.…”

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Linked Article: Henri et al Br J Dermatol 2020; 182:678-689.This issue of the BJD includes an important study by Henri et al 1 that presents details of alterations in the activity of cyclin dependent kinase (CDK)2 and CDK4 in psoriatic epidermis. Psoriasis is a chronic autoinflammatory systemic disease involving skin and joints.

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“…For all of these reasons, the study by Sbidian and colleagues may be of great importance in assisting dermatologists when considering the treatment of biologic-naive patients without specific contraindications for MTX and apremilast. 1 Future studies should investigate the efficacy and longevity of these drugs in the context of combination therapies, which have become increasingly more common in practice.…”