Abstract
The Notch/CSL pathway plays an important role in skin homeostasis and carcinogenesis. CSL, the key effector of canonical Notch signaling endowed with an intrinsic transcription repressive function, suppresses stromal fibroblast senescence and Cancer Associated Fibroblast (CAF) activation through direct down-modulation of key effector genes. Interacting proteins that participate with CSL in this context are as yet to be identified. We report here that Programmed Cell Death 4 (PDCD4), a nuclear/cytoplasmic shuttling protein with multiple functions, associates with CSL and plays a similar role in suppressing dermal fibroblast senescence and CAF activation. Like CSL, PDCD4 is down-regulated in stromal fibroblasts of premalignant skin actinic keratosis (AKs) lesions and squamous cell carcinoma (SCC). While devoid of intrinsic DNA binding capability, PDCD4 is present at CSL binding sites of CAF marker genes as well as canonical Notch/CSL targets and suppresses expression of these genes in a fibroblast-specific manner. Thus, we propose that PDCD4 is part of the CSL repressive complex involved in negative control of stromal fibroblasts conversion into CAFs.
Highlights
Notch/CSL signaling is an important form of cellcell communication with an established pro-differentiation and tumor suppressing function in the epidermal compartment of the skin [1]
The findings indicate that Programmed Cell Death 4 (PDCD4) is part of the CSL repressive complex involved in negative control of stromal fibroblasts to Cancer Associated Fibroblast (CAF) conversion
A weak but consistent association between endogenous PDCD4 and CSL was found by co-immunoprecipitation assays with nuclear extracts derived from human dermal fibroblasts (HDFs) (Figure 1A)
Summary
Notch/CSL signaling is an important form of cellcell communication with an established pro-differentiation and tumor suppressing function in the epidermal compartment of the skin [1] This pathway plays an important role in the dermal compartment. Nuclear translocation and physical binding of the activated Notch intracellular domain (NICD) converts CSL from a transcription repressor to an activator, replacing associated co-repressors with co-activators like Mastermind-like (MAML) proteins and histone acetylases (HATs) [5]. Components of these classical CSL co-repressor and co-activator complexes have been extensively studied at both functional and ultra-structural/molecular levels [6]. Additional CSL-interacting proteins are likely to exist, which may play an important role in both canonical and non-canonical Notch signaling and other cell type-specific CSL functions
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