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TGF-beta/SMAD signaling and its involvement in tumor progression
1Department of Biochemistry, The Center Institute of the Japanese Foundation for Cancer Research, Tokyo, Japan. miyazono-ind@umin.ac.jp
Abstract:
Cytokines of the transforming growth factor-beta (TGF-beta) superfamily are multifunctional peptides that regulate growth and differentiation of various types of cells. Members of the TGF-beta superfamily bind to type 11 and type I serine/threonine kinase receptors, which mediate intracellular signals through SMAD proteins. Of 3 subtypes of SMADs, receptor-regulated SMADs are phosphorylated by the serine/threonine kinase receptors, form complexes with common-mediator SMAD, and move into the nucleus, where they act as components of transcription factor complexes. Abnormalities of the TGF-beta receptors and SMADs have been detected in various tumors, including colorectal cancers and pancreatic cancers. Inhibitory SMADs and transcriptional co-repressors, including c-Ski and SnoN, repress the TGF-beta/SMAD signaling. Perturbation of the TGF-beta/SMAD signaling pathway may result in progression of tumors through resistance of the cells to the growth inhibition induced by TGF-beta.
Insights
Transforming growth factor-beta (TGF-beta) signaling regulates cell growth. Aberrant TGF-beta/SMAD pathway signaling, observed in cancers, can drive tumor progression by inhibiting cell growth responses.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Cytokines of the transforming growth factor-beta (TGF-beta) superfamily regulate cell growth and differentiation.
- TGF-beta signaling involves binding to serine/threonine kinase receptors and SMAD proteins, mediating intracellular signals.
- Dysregulation of TGF-beta receptors and SMADs is implicated in various cancers, including colorectal and pancreatic cancers.
Purpose of the Study:
- To elucidate the role of the TGF-beta/SMAD signaling pathway in cellular regulation and cancer progression.
- To highlight the significance of TGF-beta receptor and SMAD abnormalities in tumor development.
Main Methods:
- Review of molecular mechanisms of TGF-beta superfamily signaling.
- Analysis of the role of SMAD proteins in signal transduction.
- Investigation of the impact of pathway perturbation on cellular growth inhibition.
Main Results:
- Receptor-regulated SMADs are phosphorylated, complex with common-mediator SMAD, and translocate to the nucleus.
- Abnormalities in TGF-beta receptors and SMADs are linked to colorectal and pancreatic cancers.
- Inhibitory SMADs and co-repressors like c-Ski and SnoN modulate TGF-beta/SMAD signaling.
Conclusions:
- Perturbation of the TGF-beta/SMAD pathway can lead to tumor progression.
- Resistance to TGF-beta-induced growth inhibition, due to pathway dysregulation, contributes to cancer development.