Related Experiment Video
Updated: Aug 22, 2026
Detection of Aggregation-Prone Behavior in Mutant P53 V157F Breast Cancer Cells Using Multipoint Thioflavin T Fluorescence
Published on: December 30, 2025
The tumor suppressor p53 abrogates Smad-dependent collagen gene induction in mesenchymal cells
Asish K Ghosh1, Swati Bhattacharyya, John Varga
1Section of Rheumatology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60607, USA.
Abstract:
The pleiotropic cytokine transforming growth factor-beta (TGF-beta) is a potent inducer of collagen synthesis and is implicated in the pathogenesis of fibrosis. Acting in concert with transcriptional coactivators p300/CBP, the Smads mediate TGF-beta stimulation of collagen synthesis in human dermal fibroblasts. Little information exists regarding positive and negative modulation of physiological TGF-beta responses. Because the tumor suppressor p53 is implicated in connective tissue homeostasis, here we examined the regulation of collagen gene expression by p53. Forced expression of ectopic p53 in dermal fibroblasts repressed basal and TGF-beta-stimulated collagen gene expression, whereas the absence of cellular p53 was associated with significantly enhanced transcriptional activity of the Type I collagen gene (COL1A2) and collagen synthesis. Ectopic expression of p53 also repressed TGF-beta stimulation of promoter activity driven by minimal Smad-binding elements, suggesting that p53 modulated Smad-dependent intracellular signaling. Inhibition was not due to altered levels, phosphorylation, or nuclear translocation of cellular Smads. Treatment of fibroblasts with etoposide, a potent inducer of cellular p53, abrogated TGF-beta stimulation of COL1A2 promoter activity and collagen synthesis in a p53-dependent manner. Overexpression of the transcriptional coactivator p300 rescued TGF-beta stimulation of COL1A2 promoter activity in fibroblasts overexpressing p53. Furthermore, the ligand-induced interaction of cellular Smad3 with p300 or with its cognate Smad-binding DNA element and recruitment of p300 to the DNA-protein complex assembled on the Smad-binding element were markedly reduced in p53-overexpressing fibroblasts. Collectively, these results indicate, for the first time, that p53 is a potent and selective endogenous repressor of TGF-beta-regulated collagen gene expression in dermal fibroblasts. The ligand-dependent interaction of Smad3 with p300 may be one of the targets of p53-mediated inhibition of TGF-beta responses. These findings suggest that a novel and important physiologic function for the tumor suppressor p53 is the regulation of fibrotic cellular responses.
Insights
The tumor suppressor p53 inhibits transforming growth factor-beta (TGF-beta)-induced collagen production in skin cells. This discovery reveals a new role for p53 in controlling fibrotic responses and collagen gene expression.
Area of Science:
- Molecular Biology
- Cellular Biology
- Dermatology
- Oncology
Background:
- Transforming growth factor-beta (TGF-beta) is a key cytokine that stimulates collagen synthesis, playing a significant role in fibrosis.
- The Smad proteins, along with coactivators like p300/CBP, mediate TGF-beta's effects on collagen synthesis in human dermal fibroblasts.
- The precise mechanisms of positive and negative regulation of physiological TGF-beta responses are not fully understood.
Purpose of the Study:
- To investigate the role of the tumor suppressor p53 in regulating collagen gene expression.
- To determine if p53 modulates TGF-beta-induced collagen synthesis in dermal fibroblasts.
- To elucidate the molecular mechanisms by which p53 might affect TGF-beta signaling pathways.
Main Methods:
- Forced expression of ectopic p53 in human dermal fibroblasts.
- Analysis of basal and TGF-beta-stimulated Type I collagen gene (COL1A2) expression and collagen synthesis.
- Examination of Smad-dependent signaling, including promoter activity assays and protein-protein interactions.
- Utilized etoposide to induce endogenous p53 and assess its effect on TGF-beta signaling.
Main Results:
- Overexpression of p53 repressed both basal and TGF-beta-stimulated collagen gene expression and synthesis.
- Absence of cellular p53 led to enhanced COL1A2 transcriptional activity and collagen synthesis.
- p53 inhibited TGF-beta-induced promoter activity via Smad-binding elements, without altering Smad levels, phosphorylation, or nuclear translocation.
- p53 overexpression reduced the interaction between Smad3 and p300, and p300 recruitment to Smad-binding DNA elements.
Conclusions:
- p53 acts as a potent and selective endogenous repressor of TGF-beta-regulated collagen gene expression in dermal fibroblasts.
- p53 likely inhibits TGF-beta responses by interfering with the interaction between Smad3 and the coactivator p300.
- These findings identify a novel physiological function for p53 in regulating fibrotic cellular responses.
Related Concept Videos
02:23Abnormal Proliferation
01:16TGF - β Signaling Pathway
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:06Induced Pluripotent Stem Cells
Somatic cells are...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
02:36DNA Damage can Stall the Cell Cycle