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Expression, localization, and activity of glycogen synthase kinase 3beta during mouse skin tumorigenesis
Hugo Leis1, Carmen Segrelles, Sergio Ruiz
1Project on Cell and Molecular Biology, Centro de Investigaciones Energéticas Medioambientales y Technológicas (CIEMAT), Madrid, Spain.
Abstract:
Glycogen synthase kinase 3 (GSK-3) is a protein kinase that plays essential roles in the control of several developmental, metabolic, and apoptotic processes. Owing to its negative actions on several oncogenic insults, it has been considered a putative functional tumor suppressor. We studied the expression, activity, and localization of GSK-3beta during the process of chemically induced two-stage mouse skin carcinogenesis and also in the tumors generated upon subcutaneous injection of Akt-transformed keratinocytes. We found that GSK-3 activity was downregulated at the later stages of promotion by tyrosine 216 dephosphorylation and serine 9 phosphorylation. The data obtained with Akt-transformed keratinocytes clearly suggested the involvement of Akt in serine 9 phosphorylation of GSK-3beta. Finally, besides functional inactivation, significant basal activity of GSK-3beta was detected in all cases, indicating that this enzyme provides essential functions to malignant keratinocytes.
Insights
Glycogen synthase kinase 3 (GSK-3) activity decreases in later stages of skin cancer promotion. Despite inactivation, GSK-3beta maintains essential functions in malignant keratinocytes.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Glycogen synthase kinase 3 (GSK-3) is a key protein kinase involved in crucial cellular processes like development, metabolism, and apoptosis.
- GSK-3's inhibitory effects on oncogenic pathways suggest its potential role as a tumor suppressor.
Purpose of the Study:
- To investigate the expression, activity, and localization of GSK-3beta during chemically induced mouse skin carcinogenesis.
- To examine GSK-3beta's role in tumors formed by Akt-transformed keratinocytes.
Main Methods:
- Studied GSK-3beta expression, activity, and localization in mouse skin carcinogenesis models.
- Utilized Akt-transformed keratinocytes to assess Akt's influence on GSK-3beta.
Main Results:
- GSK-3 activity was found to be downregulated in later stages of skin cancer promotion.
- Downregulation occurred via tyrosine 216 dephosphorylation and serine 9 phosphorylation.
- Akt was implicated in the serine 9 phosphorylation of GSK-3beta.
- Significant basal GSK-3beta activity was observed even in inactivated states within malignant keratinocytes.
Conclusions:
- GSK-3beta undergoes functional inactivation during skin carcinogenesis, particularly at later stages.
- The Akt signaling pathway contributes to GSK-3beta inactivation.
- Despite inactivation, GSK-3beta retains essential functions necessary for the survival and proliferation of malignant keratinocytes.