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Transforming growth factor-beta 1 stimulates or inhibits cell growth via down- or up-regulation of p21/Waf1
M Miyazaki1, R Ohashi, T Tsuji
1Department of Cell Biology, Okayama University Medical School, Japan. hiromiya@med.okayama-u.ac.jp
Abstract:
Transforming growth factor-beta (TGF-beta) regulates cell proliferation positively or negatively. The mitoinhibition by TGF-beta has been attributed to induction of cyclin-dependent kinase (CDK) inhibitors, such as p15/ Ink4B, p27/Kip1, and p21/Waf1 also known as Cip1 and Sdi1. However, the biological process by which TGF-beta exerts the stimulatory effects on cell growth remains poorly understood. Here we report that TGF-beta 1 stimulates DNA synthesis of IMR-90 human embryonic lung fibroblasts but inhibits that of HuCCT1 human cholangiocarcinoma cells, via down- or up-regulation of p21/Waf1, respectively. TGF-beta 1 markedly suppresses IMR-90 cells to express two different kinds of the p21/Waf1 gene transcription factors, the p53 tumor suppressor and the interferon regulatory factor-1 (IRF-1). This is followed by a marked decrease in expression of p21/Waf1 in a manner consistent with the timing of activation of cyclin E-associated kinase, which normally accompanies the G1-S transition in the cell cycle. Contrarily, TGF-beta 1-induced inhibition of DNA synthesis in HuCCT1 cells is preceded by IRF-1-dependent but p53-independent up-regulation of p21/Waf1 expression followed by inactivation of cyclin E-associated kinase. Thus the cell growth stimulation or inhibition by TGF-beta 1 are mediated by the down- or up-regulation of p21/ Waf1, respectively.
Insights
Transforming growth factor-beta (TGF-beta) differentially regulates cell proliferation by modulating p21/Waf1 expression. TGF-beta 1 stimulates DNA synthesis in IMR-90 cells via p21/Waf1 down-regulation, but inhibits HuCCT1 cells through its up-regulation.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor-beta (TGF-beta) is a key regulator of cell proliferation, with known roles in both growth inhibition and stimulation.
- TGF-beta-induced cell cycle arrest is often mediated by cyclin-dependent kinase (CDK) inhibitors, including p21/Waf1 (also known as Cip1 and Sdi1).
- The precise mechanisms by which TGF-beta influences cell growth stimulation remain less understood compared to its inhibitory effects.
Purpose of the Study:
- To elucidate the distinct molecular mechanisms underlying TGF-beta 1-mediated cell proliferation in different cell types.
- To investigate the role of p21/Waf1 and its associated transcription factors (p53 and IRF-1) in mediating TGF-beta 1's opposing effects on DNA synthesis.
- To differentiate the pathways of TGF-beta 1 action in normal fibroblasts versus cancer cells.
Main Methods:
- Comparative analysis of TGF-beta 1 effects on DNA synthesis in IMR-90 (human embryonic lung fibroblasts) and HuCCT1 (human cholangiocarcinoma) cells.
- Quantitative assessment of p21/Waf1, p53, and interferon regulatory factor-1 (IRF-1) gene and protein expression levels.
- Monitoring of cyclin E-associated kinase activity to correlate with cell cycle progression.
Main Results:
- TGF-beta 1 stimulated DNA synthesis in IMR-90 cells by down-regulating p21/Waf1 expression, which was linked to suppressed expression of p53 and IRF-1.
- In contrast, TGF-beta 1 inhibited DNA synthesis in HuCCT1 cells via IRF-1-dependent, p53-independent up-regulation of p21/Waf1.
- These changes in p21/Waf1 levels correlated with the activation status of cyclin E-associated kinase, indicating cell cycle modulation.
Conclusions:
- Cellular response to TGF-beta 1, whether proliferative or inhibitory, is critically dependent on the differential regulation of p21/Waf1 expression.
- The interplay between TGF-beta 1, p53, IRF-1, and p21/Waf1 dictates the outcome on cell cycle progression and DNA synthesis.
- Understanding these distinct pathways offers insights into TGF-beta's complex roles in normal tissue homeostasis and cancer development.