TY - JOUR
T1 - Inhibition of β-TrCP function potentiates UVB-induced apoptosis in hTERT-immortalized normal human keratinocytes
AU - Bhatia, Neehar
AU - Demmer, Tara A.
AU - Spiegelman, Vladimir
PY - 2008/3
Y1 - 2008/3
N2 - Chronic skin exposure to UV radiation manifests in a score of biochemical events, DNA damage and mutations which can potentially cause skin cancer. The ubiquitin proteasome pathway controls the degradation of a majority of regulatory eukaryotic proteins including those which play a key role in tumorigenesis. SCFβTrCP E3 ubiquitin ligases mediate ubiquitination and proteasomal degradation of phosphorylated substrates that play a key role in signal transduction. Activation of several signaling pathways involved in tumorigenesis was shown to elevate expression and activity of β-TrCP1/2. In this study, we established and characterized human neonatal foreskin keratinocytes, rendered immortal by retroviral introduction of human telomerase reverse transcriptase (hTERT). These skin hTERT immortalized normal keratinocytes (STINKs) maintain characteristic traits of keratinocytes, such as expression of keratins, cytoplasmic localization of basonuclin and susceptibility to high concentration of calcium. We analyzed the response of STINKs to UVB radiation and its classical markers, such as p53 and nuclear factor (NF)-κB. We also demonstrate that inhibition of β-TrCP2 function, by induction of dominant negative β-TrCP2 (β-TrCP2 ΔN), accentuates UVB induced apoptosis, and this phenomenon is independent of NF-κB and p53 pathways.
AB - Chronic skin exposure to UV radiation manifests in a score of biochemical events, DNA damage and mutations which can potentially cause skin cancer. The ubiquitin proteasome pathway controls the degradation of a majority of regulatory eukaryotic proteins including those which play a key role in tumorigenesis. SCFβTrCP E3 ubiquitin ligases mediate ubiquitination and proteasomal degradation of phosphorylated substrates that play a key role in signal transduction. Activation of several signaling pathways involved in tumorigenesis was shown to elevate expression and activity of β-TrCP1/2. In this study, we established and characterized human neonatal foreskin keratinocytes, rendered immortal by retroviral introduction of human telomerase reverse transcriptase (hTERT). These skin hTERT immortalized normal keratinocytes (STINKs) maintain characteristic traits of keratinocytes, such as expression of keratins, cytoplasmic localization of basonuclin and susceptibility to high concentration of calcium. We analyzed the response of STINKs to UVB radiation and its classical markers, such as p53 and nuclear factor (NF)-κB. We also demonstrate that inhibition of β-TrCP2 function, by induction of dominant negative β-TrCP2 (β-TrCP2 ΔN), accentuates UVB induced apoptosis, and this phenomenon is independent of NF-κB and p53 pathways.
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U2 - 10.1111/j.1751-1097.2007.00272.x
DO - 10.1111/j.1751-1097.2007.00272.x
M3 - Article
C2 - 18208454
AN - SCOPUS:41049095847
VL - 84
SP - 376
EP - 381
JO - Photochemistry and Photobiology
JF - Photochemistry and Photobiology
SN - 0031-8655
IS - 2
ER -