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Published on: January 27, 2012
Cell division cycle 7 kinase is a negative regulator of cell-mediated collagen degradation
Michael J Podolsky1, Deepti Gupta1, Arnold Ha1
1Department of Medicine, Lung Biology Center, Cardiovascular Research Institute, University of California, San Francisco, California.
Abstract:
Although extensive work has delineated many of the mechanisms of extracellular matrix (ECM) production, far less is known about pathways that regulate ECM degradation. This is particularly true of cellular internalization and degradation of matrix, which play an underappreciated role in ECM metabolism and lung fibrosis. For example, genetic perturbation of this pathway leads to exacerbated fibrosis in experimental animal models. In this work, we present the results of an unbiased screen of Drosophila phagocytes that yielded multiple genes that, when silenced, led to increased collagen uptake. We further describe the function of cell division cycle 7 kinase (CDC7) as a specific suppressor of collagen uptake. We show that the genetic or pharmacological inhibition of CDC7 results in increased expression of the collagen endocytic receptor Endo180. Chromobox 5 (CBX5) is a putative target of CDC7, and genetic silencing of CBX5 also results in increased Endo180 and collagen uptake. Finally, CRISPR-mediated activation of Endo180 expression results in increased collagen uptake, suggesting that CDC7 regulates collagen internalization through increased Endo180 expression. Targeting the regulatory elements of the collagen degradative machinery may be a useful therapeutic approach in diseases of fibrosis or malignancy.
Insights
Researchers identified key genes regulating collagen uptake in Drosophila, revealing cell division cycle 7 kinase (CDC7) as a suppressor of this process. Inhibiting CDC7 increases collagen internalization, offering potential therapeutic targets for fibrosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Extracellular matrix (ECM) production is well-studied, but ECM degradation mechanisms, especially cellular internalization and degradation, are less understood.
- These degradation pathways are crucial for ECM metabolism and play a significant role in lung fibrosis.
- Genetic disruption of ECM degradation pathways can worsen fibrosis in animal models.
Purpose of the Study:
- To identify genes regulating cellular internalization and degradation of the extracellular matrix.
- To elucidate the role of cell division cycle 7 kinase (CDC7) in collagen uptake.
- To explore the molecular mechanisms by which CDC7 influences collagen internalization.
Main Methods:
- Conducted an unbiased genetic screen of Drosophila phagocytes to identify genes affecting collagen uptake.
- Utilized genetic and pharmacological inhibition of CDC7.
- Investigated the expression of the collagen endocytic receptor Endo180.
- Examined the role of Chromobox 5 (CBX5) as a potential target of CDC7.
- Employed CRISPR-mediated activation of Endo180 expression.
Main Results:
- An unbiased screen identified multiple genes that, when silenced, increased collagen uptake by Drosophila phagocytes.
- Cell division cycle 7 kinase (CDC7) was identified as a specific suppressor of collagen uptake.
- Inhibition of CDC7 led to increased expression of the collagen endocytic receptor Endo180.
- Silencing of Chromobox 5 (CBX5) also resulted in increased Endo180 and collagen uptake, suggesting it is a target of CDC7.
- CRISPR-mediated activation of Endo180 expression increased collagen uptake.
Conclusions:
- CDC7 regulates collagen internalization, at least in part, by modulating Endo180 expression.
- Targeting regulatory elements of the collagen degradation machinery presents a potential therapeutic strategy for fibrotic diseases and malignancies.
- The findings highlight the underappreciated role of cellular ECM degradation in fibrosis and provide new molecular targets.
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