c-Rel in Epidermal Homeostasis: A Spotlight on c-Rel in Cell Cycle Regulation

Abstract

To maintain proper skin barrier function, epidermal homeostasis requires a subtly governed balance of proliferating and differentiating keratinocytes. While differentiation takes place in the suprabasal layers, proliferation, including mitosis, is usually restricted to the basal layer. Only recently identified as an important regulator of epidermal homeostasis, c-Rel, an NF-κB transcription factor subunit, affects the viability and proliferation of epidermal keratinocytes. In human keratinocytes, decreased expression of c-Rel causes a plethora of dysregulated cellular functions including impaired cell viability, increased apoptosis, and abnormalities during mitosis and cell cycle regulation. On the other hand, c-Rel shows aberrant expression in many epidermal tumors. Here, in the context of its role in different cell types and compared with other NF-κB subunits, we discuss the putative function of c-Rel as a regulator of epidermal homeostasis and mitotic progression. In addition, implications for disease pathophysiology with perturbed c-Rel function and abnormal homeostasis, such as epidermal carcinogenesis, will be discussed.

c‐Rel is a cell cycle modulator in human melanoma cells

“…Expression of c‐Rel in human melanoma has been described previously . However, when analysing c‐Rel expression in primary human melanoma samples, a heterogeneous staining pattern became obvious in a subset of primary and metastatic melanoma.…”

“…Expression of c-Rel in human melanoma has been described previously. [26] However, when analysing c-Rel expression in primary human melanoma samples, a heterogeneous staining pattern became obvious in a subset of primary and metastatic melanoma. On a cellular level, c-Rel expression was found in 20% of studied primary human melanomas in a striking intensity especially in mitotic figures of atypical melanocytes as exemplarily highlighted in the enlarged detail (arrows Figure 1A).…”

“…Initially, only defects in T‐ and B‐lymphocyte functions were identified in c‐rel −/− mice . While other functions of c‐Rel have only recently emerged and include hepatocyte wound healing, cardiac hypertrophy, cognitive memory formation and epidermal homeostasis …”

“…[18,19] While other functions of c-Rel have only recently emerged [20] and include hepatocyte wound healing, [21] cardiac hypertrophy, [22] cognitive memory formation [23] and epidermal homeostasis. [24][25][26] Of note, elevated c-Rel expression was found in human melanoma compared to normal skin and benign naevi, [27] but a functional role could not be discerned from these descriptive studies.…”

Intersection of the p63 and NF‐κB pathways in epithelial homeostasis and disease

“…This association was confirmed in cell lines derived from head and neck squamous cell carcinomas (HNSCCs), suggesting that this association may contribute to the aberrant regulation associated with human cancers. Roles for the NF‐κB subunits were initially recognized in B‐cells but it has subsequently become apparent that this family of transcription factors is expressed in a broad range of tissue types and impacts a variety of biological pathways, including those involved in skin homeostasis and cutaneous carcinogenesis . The current review provides an overview of the p63 and NF‐κB/c‐Rel transcription factors in squamous epithelium and highlights current understanding regarding how their pathways converge in squamous cancer pathogenesis.…”