| Summary: | 博士 === 長庚大學 === 臨床醫學研究所 === 105 === -Part 1-
The dermal papilla, located in the hair follicle, expresses androgen receptor and plays an important role in hair growth. Androgen/Androgen receptor (AR) actions have been implicated in the pathogenesis of androgenetic alopecia (AGA), but the exact mechanism is not well known. Recent studies suggest that balding dermal papilla cells (DPCs) exhibit premature senescence, upregulation of p16INK4a, and nuclear expression of DNA damage markers. To investigate whether androgen/AR signaling influences the premature senescence of DPCs, we first compared frontal scalp DPCs of AGA patients with matched normal controls and observed that premature senescence is more prominent in the DPCs of AGA patients. Exposure of androgen induced premature senescence in DPCs from non-balding frontal and transitional zone of balding scalp follicles but not in beard follicles. Overexpression of the AR promoted androgen-induced premature senescence in association with p16INK4a upregulation, whereas knockdown of the androgen receptor diminished the effects of androgen. An analysis of γ-H2AX expression in response to androgen/androgen receptor signaling suggested that DNA damage contributes to androgen/AR-accelerated premature senescence. These results define androgen/AR signaling as an accelerator of premature senescence in DPCs and suggest that the androgen/AR-mediated DNA damage-p16INK4a axis is a potential therapeutic target in the treatment of AGA.
-Part 2-
Commitment of differentiating embryonic stem cells (ESCs) toward the various lineages and cell death is influenced by many factors, including androgens. However, the mechanisms underlying proteotoxic stress conferred by androgen receptor (AR) actions on embryonic cell fate remains unclear. Here we show that mouse ESCs display stress-related cellular phenotypes in response to androgens during early phase of differentiation. Androgen induced a significant increase in the percentage of ESCs and EBs (Embryonic bodies) with the intranuclear and juxtanuclear AR inclusions that were co-localized with the E3 ubiquitin ligase CHIP. Caspase-3 activity corresponded with AR expression, was enhanced in cells engaged more differentiation phenotypes. Androgen-mediated accumulation of AR aggregates exacerbated endoplasmic reticulum (ER) stress and rendered ESCs susceptible to apoptosis. Increasing expression levels of the ER chaperones, GRP78 and GRP94, as well as ER stress markers such as ATF6, phosphorylated PERK, CHOP and spliced XBP-1 were dramatically elevated in ESCs overexpressing AR. HsP40, HsP70, GRP78 and GRP94 also interacted with AR in ESCs. Overexpression of GRP78 suppressed ubiquitination of AR aggregates and ameliorated the misfolded AR-mediated cytopathology in ESCs, whereas knockdown of GRP78 increased the accumulation of AR aggregates and significantly higher levels of caspase 3 activity and cell apoptosis. These results generate novel insight into how ESCs respond to stress induced by androgen/AR and differentiation.
|
|---|
