TY - JOUR
T1 - Novel initiation genes in squamous cell carcinomagenesis
T2 - A role for substrate-specific ubiquitylation in the control of cell survival
AU - Albor, Amador
AU - Kulesz-Martin, Molly
PY - 2007/8
Y1 - 2007/8
N2 - The study of experimental epidermal carcinogenesis offers several advantages over other epithelial carcinogenesis models, including easy accessibility and a database of research findings spanning over a century. Our studies make use of a clonal in vitro/in vivo keratinocyte carcinogenesis model with low frequency of ras mutation and derivative clonal-initiated lineages with distinct tumor fate. Analysis of this model has yielded candidate genes involved in the stages of initiation and tumorigenic progression, and has revealed novel roles for ubiquitylation in transcriptional control of survival and apoptotic pathways during the early stages of carcinogenesis. The expression of a recently described E3-ubiquitin ligase, Trim32, is elevated during initiation, and ectopic expression of Trim32 confers extended survival in response to terminal differentiation and ultraviolet light (UV) B/TNF-α death signals. Trim32 binds and ubiquitylates Piasy, controlling its stability and accumulation. Piasy is a SUMOylation factor involved in the control of apoptosis, senescence, and NF-κB activation. NF-κB is a survival factor for keratinocytes in response to UV irradiation, the main carcinogenic stimulus for the epidermis. Piasy inhibits NF-κB activity, and promotes keratinocyte apoptosis in response to UV and TNF-α. In human skin squamous cell carcinoma (SCC) samples, we found an inverse correlation between Trim32 and Piasy expression supporting a role for Trim32-Piasy interaction in human epidermal carcinogenesis. Our hypothesis is that increased expression of Trim32 may enhance epidermal carcinogenesis, by increasing the threshold of NF-κB activity through Piasy downmodulation.
AB - The study of experimental epidermal carcinogenesis offers several advantages over other epithelial carcinogenesis models, including easy accessibility and a database of research findings spanning over a century. Our studies make use of a clonal in vitro/in vivo keratinocyte carcinogenesis model with low frequency of ras mutation and derivative clonal-initiated lineages with distinct tumor fate. Analysis of this model has yielded candidate genes involved in the stages of initiation and tumorigenic progression, and has revealed novel roles for ubiquitylation in transcriptional control of survival and apoptotic pathways during the early stages of carcinogenesis. The expression of a recently described E3-ubiquitin ligase, Trim32, is elevated during initiation, and ectopic expression of Trim32 confers extended survival in response to terminal differentiation and ultraviolet light (UV) B/TNF-α death signals. Trim32 binds and ubiquitylates Piasy, controlling its stability and accumulation. Piasy is a SUMOylation factor involved in the control of apoptosis, senescence, and NF-κB activation. NF-κB is a survival factor for keratinocytes in response to UV irradiation, the main carcinogenic stimulus for the epidermis. Piasy inhibits NF-κB activity, and promotes keratinocyte apoptosis in response to UV and TNF-α. In human skin squamous cell carcinoma (SCC) samples, we found an inverse correlation between Trim32 and Piasy expression supporting a role for Trim32-Piasy interaction in human epidermal carcinogenesis. Our hypothesis is that increased expression of Trim32 may enhance epidermal carcinogenesis, by increasing the threshold of NF-κB activity through Piasy downmodulation.
KW - Carcinogenesis
KW - E3-ubiquitin ligase
KW - Piasy
KW - Protein degradation
KW - Trim family scaffold proteins
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U2 - 10.1002/mc.20344
DO - 10.1002/mc.20344
M3 - Article
C2 - 17626251
AN - SCOPUS:34547916840
SN - 0899-1987
VL - 46
SP - 585
EP - 590
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
IS - 8
ER -