Pituitary Tumor Transforming Gene 1 Induces Tumor Necrosis Factor-α Production from Keratinocytes: Implication for Involvement in the Pathophysiology of Psoriasis

Abstract

Proliferation and differentiation in the epidermis must be tightly regulated. This regulation is known to involve a range of transcription factors, including pituitary tumor transforming gene 1 (PTTG1), a ubiquitously distributed transcription factor that regulates keratinocyte proliferation and differentiation. Psoriasis is a common but refractory skin disorder, the pathophysiology of which is characterized by hyperproliferation and impaired differentiation in the epidermis. The present study was conducted to clarify the less well-known roles of PTTG1 in the pathophysiology of psoriasis, focusing on its relationship with tumor necrosis factor-α (TNF-α), which is a critical mediator of the disease. The levels of PTTG1 expression were increased in the psoriatic epidermis. Overexpression of PTTG1 resulted in the overproduction of TNF-α, and TNF-α itself had an inductive effect on PTTG1 expression, suggesting that their expression may involve autoinduction. Moreover, overexpression of PTTG1 involved augmented the expression of cyclin A and B1 proteins in both cultured keratinocytes and the psoriatic epidermis. Therefore, enhanced expression of PTTG1 in the psoriatic epidermis may result in aberrant regulation of the cell cycle and impaired differentiation via the interplay between PTTG1 and TNF-α.

PTTG1 is involved in TNF‐α‐related hepatocellular carcinoma via the induction of c‐myc

“…TNF‐α plays a vital role in cancer by promoting the aberrant expression of a variety of genes through signaling pathway activation . The proinflammatory cytokine TNF‐α, which is mainly secreted by macrophages, can induce PTTG1 mRNA and protein expression in a dose‐dependent manner in keratinocytes . Our study showed that TNF‐α was upregulated in both HCC and paracancer tissues compared with normal liver tissues.…”

“…During hepatocellular carcinogenesis, TNF‐α induces persistent hepatocyte proliferation, increases the malignant transformation of normal hepatocytes and promotes the expression of various oncogenes . In keratinocytes, TNF‐α leads to the induction of PTTG1 expression . However, there is limited knowledge of the exact mechanisms of TNF‐α‐induced PTTG1 involvement in hepatocellular carcinogenesis.…”

“…8 In keratinocytes, TNF-α leads to the induction of PTTG1 expression. 9 However, there is limited knowledge of the exact mechanisms of TNF-α-induced PTTG1 involvement in hepatocellular carcinogenesis.…”

Zinc finger protein A20 is involved in the antipsoriatic effect of calcipotriol

“…There might be several reasons for such findings. Firstly, A20 is TNF‐α‐inducible while TNF‐α is robustly produced in psoriatic skins . Secondly, NF‐κB activation in psoriasis induces A20 expression through a feedback mechanism.…”

“…Firstly, A20 is TNF-a-inducible while TNF-a is robustly produced in psoriatic skins. 33 Secondly, NF-jB activation in psoriasis induces A20 expression through a feedback mechanism. Finally, psoriatic inflammation may switch keratinocytes from an apoptotic to a proliferative fate under activation of certain signals that usually induce apoptosis of keratinocytes under nonpsoriatic conditions.…”