Psoriatic epidermis is associated with upregulation of CDK 2 and inhibition of CDK 4 activity

Abstract

Summary Background The cyclin‐dependent kinases (CDKs) CDK2 and CDK4 are involved in regulation of cell‐cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. CDK inhibitory proteins (CKIs) such as p16INK4A (p16) bind CDK4/6 kinases and prevent their interaction with D‐type cyclins. CKIs such as p21Cip1 (p21) and p27Kip1 (p27) associate with CDK–cyclin complexes and prevent their activation. Objectives To gain insight into the molecular implication of CDK2 and CDK4 kinases in psoriasis, we sought to characterize expression of these kinases and associated cyclins, as well as of CKIs, and addressed the status of CDK2 and CDK4 activity in human psoriatic epidermis. Methods A cohort of 24 patients with psoriasis participated in the study. Biopsies were removed from a chronic plaque and from nonlesional skin. CDK2, CDK4, cyclin D1, cyclin E and CKI protein expression was assessed by immunoblotting, immunohistochemistry and immunofluorescence. CDK4 and CDK2 mRNA expression was determined by real‐time polymerase chain reaction. Specific kinase activities of CDK2 and CDK4 were evaluated using fluorescent peptide biosensors. Results CDK2–cyclin E expression and activity were significantly increased in psoriatic epidermis compared with uninvolved adjacent skin. In contrast, CDK4–cyclin D1 activity was inhibited, although its expression was increased in psoriatic epidermis and its transcription slightly inhibited. p27 expression was reduced, while p16 and p21 expression was induced in psoriatic epidermis. Conclusions Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post‐translational control mediated by decreased expression of p27 and p16 overexpression, respectively. What's already known about this topic? Cyclin‐dependent kinases (CDKs) are involved in cell‐cycle progression. The levels of cyclin partners and CDK inhibitors regulate their activity. Psoriasis is a chronic T‐cell‐driven inflammatory skin disease characterized by hyperproliferation of basal epidermal cells. What does this study add? Thanks to fluorescent peptide biosensors, this study demonstrates that epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations involve post‐translational control mediated by decreased expression of p27, and p16 overexpression, respectively. What is the translational message? CDK2 and CDK4 are involved in regulation of cell‐cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post‐translational control mediated by decreased expression of p27 and p16 overexpression, respectively. Pharmacological modulation of CDK2 and CDK4 may c...

Intracellular Insulin-like growth factor binding protein 2 (IGFBP2) contributes to the senescence of keratinocytes in psoriasis by stabilizing cytoplasmic p21

“…We provide evidence that the unphosphorylated form of p21 accumulated in vivo in the nuclear compartment of keratinocytes located in the suprabasal, senescent layers of psoriatic lesions, and this is a typical feature of senescent cells, as recently demonstrated [19]. Interestingly, in line with previous reports, we found that phosphorylated p21 (Ser146) was mainly distributed in the cytoplasm of senescent cells, where it co-localized with IGFBP2 (Figure 8).…”

“…Consistent with IGFBP2, p16 expression was weakly detectable in the epidermis of distant NLS of psoriatic patients (i), and absent in healthy controls (iv) or in the skin of AD patients (v). In line with a recent in vivo study [19], we found that the number of p21 positive cells progressively increased through the transition from Pre-LS ( Figure 2A, ii) to LS (iii) skin, where p21 localization was mainly observed in the nucleus of keratinocytes of the spinous layers of epidermis ( Figure 2A). p21 staining was undetectable in healthy epidermis (iv), and weakly detected in a low number of keratinocytes within NLS (i) and AD (v) epidermis.…”

“…At the molecular level, senescence is characterized by an enhanced expression of proteins involved in regulation of cell cycle, including cyclin-dependent kinase inhibitors p16INK4a (p16) and p21CIP1/WAF1 (p21) [16][17][18][19]. In particular, p16 binds to cyclindependent kinases (CDK)4/6 and abrogates their binding to cyclin D1, thereby determining cell cycle arrest in G1 phase.…”

Stress-Related Regulation Is Abnormal in the Psoriatic Uninvolved Skin

“…In that same study p27/CDKN1B showed decreased expression in nonlesional epidermis, but, in some cases, immunolabeled nuclei for p27 in the uppermost keratinocytes were also observed [ 30 ]. Another study described that the expression of p27/CDKN1B was increased in the uninvolved skin compared to involved skin based on immunostaining [ 31 ]. In our present study, we detected enhanced nuclear positivity of the p27/CDKN1B in the upper layers of the psoriatic uninvolved epidermis and this nuclear positivity showed a negative correlation with disease severity.…”

Expression Patterns of Clock Gene mRNAs and Clock Proteins in Human Psoriatic Skin Samples

“…CLOCK/BMAL1 protein complex and PER2 regulate cell cycle checkpoints, whose overexpression is involved in epidermal turnover [ 64 ]. In psoriasis, altered distributions can be seen in cell cycle regulatory proteins, CDK2 and cyclin E expression, which cause hyperproliferation and are upregulated in the upper layers of the epidermis [ 65 , 66 ].…”