NF-κB RelA opposes epidermal proliferation driven by TNFR1 and JNK

Abstract

NF-B inhibition promotes epidermal tumorigenesis; however, whether this reflects an underlying role in homeostasis or a special case confined to neoplasia is unknown. Embryonic lethality of mice lacking NF-B RelA has hindered efforts to address this. We therefore generated developmentally mature RelA −/− skin. RelA −/− epidermis displays hyperplasia without abnormal differentiation, inflammation, or apoptosis. Hyperproliferation is TNFR1-dependent because Tnfr1 deletion normalized cell division. TNFR1-dependent JNK activation occurred in RelA −/− epidermis, and JNK inhibition abolished hyperproliferation due to RelA deficiency. Thus, RelA antagonizes TNFR1-JNK proliferative signals in epidermis and plays a nonredundant role in restraining epidermal growth.Supplemental material is available at http://www.genesdev.org.

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…For example, one report demonstrated that inhibition of NF-kB in skin leads to oncogenic potential and potentiates H-Rasinduced transformation (Dajee et al, 2003). One mechanism to explain this concept is that inhibition of NF-kB in the skin leads to JNK activation (Zhang et al, 2004), a finding consistent with several reports that NF-kB activation suppresses the phosphorylation and activation of JNK.…”

Proliferation and cornification during development of the mammalian epidermis

“…p65/RelA Ϫ/Ϫ, TNFR Ϫ/Ϫ epidermis lacked hyperplasia and displayed normal levels of CDK4 (Zhang et al, 2005) and JNK (Zhang et al, 2004). Pharmacological treatment of p65/RelA-deficient epidermis with a topical JNK inhibitor decreased levels of activated JNK and reversed the epidermal hyperplasia (Zhang et al, 2004). Together, these findings indicate that NF-B opposes the pro-liferative activity of TNFR1/JNK during epidermal development (see Fig.…”

“…Mouse epidermis and E14.5 keratinocytes deficient for p65/RelA display marked hyperplasia/proliferation, increased levels of active, nuclear c-jun NH 2 -terminal kinase (JNK1/2), and a significant increase in protein levels of cyclin-dependent kinase 4 (CDK4) (Zhang et al, 2004(Zhang et al, , 2005. JNK, a member of the MAP kinase family, is activated by tumor necrosis factor cell surface receptor, TNFR1 (as is NF-B), and participates in numerous cellular processes, including proliferation (reviewed in Aggarwal, 2000;Ghosh and Karin, 2002).…”

“…The hyperplasia observed in p65/ RelA Ϫ/Ϫ epidermis was shown to be dependant on intact TNFR1, and increased JNK and CDK4 activity. p65/RelA Ϫ/Ϫ, TNFR Ϫ/Ϫ epidermis lacked hyperplasia and displayed normal levels of CDK4 (Zhang et al, 2005) and JNK (Zhang et al, 2004). Pharmacological treatment of p65/RelA-deficient epidermis with a topical JNK inhibitor decreased levels of activated JNK and reversed the epidermal hyperplasia (Zhang et al, 2004).…”

“…While NF-B functions to induce growth arrest in epidermal keratinocytes, it does not influence the expression of differentiation markers (Seitz et al, 1998;Zhang et al, 2004). Thus, it is intriguing to note that in vitro and in vivo human and mouse studies indicate that NF-B may actually prevent a default apoptotic pathway in epithelial cells that are preparing to undergo the more specialized forms of programmed cell death (Qin et al, 1999;Seitz et al, 2000b).…”