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Coordination of cell proliferation and cell fate determination by CES-1 snail.

Yan B, Memar N, Gallinger J, Conradt B - PLoS Genet. (2013)

Bottom Line: We now demonstrate that CES-1 also affects cell cycle progression in this lineage.Finally, we provide evidence that dnj-11 MIDA1 not only regulate CES-1 activity in the context of cell polarity and apoptosis but also in the context of cell cycle progression.In mammals, the over-expression of Snail-related genes has been implicated in tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrated Protein Science, Department of Biology II, Ludwig-Maximilians-University, Munich, Planegg-Martinsried, Germany ; Department of Genetics, MCB Graduate Program, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

ABSTRACT
The coordination of cell proliferation and cell fate determination is critical during development but the mechanisms through which this is accomplished are unclear. We present evidence that the Snail-related transcription factor CES-1 of Caenorhabditis elegans coordinates these processes in a specific cell lineage. CES-1 can cause loss of cell polarity in the NSM neuroblast. By repressing the transcription of the BH3-only gene egl-1, CES-1 can also suppress apoptosis in the daughters of the NSM neuroblasts. We now demonstrate that CES-1 also affects cell cycle progression in this lineage. Specifically, we found that CES-1 can repress the transcription of the cdc-25.2 gene, which encodes a Cdc25-like phosphatase, thereby enhancing the block in NSM neuroblast division caused by the partial loss of cya-1, which encodes Cyclin A. Our results indicate that CDC-25.2 and CYA-1 control specific cell divisions and that the over-expression of the ces-1 gene leads to incorrect regulation of this functional 'module'. Finally, we provide evidence that dnj-11 MIDA1 not only regulate CES-1 activity in the context of cell polarity and apoptosis but also in the context of cell cycle progression. In mammals, the over-expression of Snail-related genes has been implicated in tumorigenesis. Our findings support the notion that the oncogenic potential of Snail-related transcription factors lies in their capability to, simultaneously, affect cell cycle progression, cell polarity and apoptosis and, hence, the coordination of cell proliferation and cell fate determination.

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ces-1 Snail represents a functional link between cell cycle progression, cell polarity and apoptosis in the NSM lineage.Genetic model of ces-1 Snail functions in the NSM neuroblast (top), the NSM and the NSM sister cell (bottom). In the NSM neuroblast, ces-1 function is negatively regulated by the genes dnj-11 MIDA1 and ces-2 bZIP. ces-1 affects cell cycle progression in the NSM neuroblast by negatively regulating cdc-25.2 Cdc25. ces-1 also affects the polarity of the NSM neuroblast. However, to date, it is unclear through what mechanism. After the asymmetric division of the NSM neuroblast, the level of ces-1 activity is high in the larger NSM (left) and low in the smaller NSM sister cell (right). The activity of ces-1 in the NSM is sufficient to block the function of hlh-2/3 bHLH, thereby resulting in a level of egl-1 BH3-only activity that is too low to induce apoptosis. Conversely, in the NSM sister cell, the activity of ces-1 is not sufficient to block the function of hlh-2/3, thereby resulting in a level of egl-1 activity that is high enough to induce apoptosis. See text for details and molecular interpretations.
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pgen-1003884-g006: ces-1 Snail represents a functional link between cell cycle progression, cell polarity and apoptosis in the NSM lineage.Genetic model of ces-1 Snail functions in the NSM neuroblast (top), the NSM and the NSM sister cell (bottom). In the NSM neuroblast, ces-1 function is negatively regulated by the genes dnj-11 MIDA1 and ces-2 bZIP. ces-1 affects cell cycle progression in the NSM neuroblast by negatively regulating cdc-25.2 Cdc25. ces-1 also affects the polarity of the NSM neuroblast. However, to date, it is unclear through what mechanism. After the asymmetric division of the NSM neuroblast, the level of ces-1 activity is high in the larger NSM (left) and low in the smaller NSM sister cell (right). The activity of ces-1 in the NSM is sufficient to block the function of hlh-2/3 bHLH, thereby resulting in a level of egl-1 BH3-only activity that is too low to induce apoptosis. Conversely, in the NSM sister cell, the activity of ces-1 is not sufficient to block the function of hlh-2/3, thereby resulting in a level of egl-1 activity that is high enough to induce apoptosis. See text for details and molecular interpretations.

Mentions: CES-1 has previously been shown to cause loss of cell polarity in the NSM neuroblast and to suppress apoptosis in its daughter cells [17], [19]. Through a combination of genetic and cell biological studies, we now show that CES-1 also affects cell cycle progression in the NSM neuroblast (See model, Figure 6). In one and the same cell lineage and within a short period of time (<150 min), CES-1 therefore impacts on at least three processes (cell cycle progression, cell polarity and apoptosis) that are fundamentally important to normal development. We speculate that it is through their ability to impact on these processes in a spatially and temporally coordinated manner that Snail-related transcription factors play a crucial role in normal development and tumorigenesis.


Coordination of cell proliferation and cell fate determination by CES-1 snail.

Yan B, Memar N, Gallinger J, Conradt B - PLoS Genet. (2013)

ces-1 Snail represents a functional link between cell cycle progression, cell polarity and apoptosis in the NSM lineage.Genetic model of ces-1 Snail functions in the NSM neuroblast (top), the NSM and the NSM sister cell (bottom). In the NSM neuroblast, ces-1 function is negatively regulated by the genes dnj-11 MIDA1 and ces-2 bZIP. ces-1 affects cell cycle progression in the NSM neuroblast by negatively regulating cdc-25.2 Cdc25. ces-1 also affects the polarity of the NSM neuroblast. However, to date, it is unclear through what mechanism. After the asymmetric division of the NSM neuroblast, the level of ces-1 activity is high in the larger NSM (left) and low in the smaller NSM sister cell (right). The activity of ces-1 in the NSM is sufficient to block the function of hlh-2/3 bHLH, thereby resulting in a level of egl-1 BH3-only activity that is too low to induce apoptosis. Conversely, in the NSM sister cell, the activity of ces-1 is not sufficient to block the function of hlh-2/3, thereby resulting in a level of egl-1 activity that is high enough to induce apoptosis. See text for details and molecular interpretations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814331&req=5

pgen-1003884-g006: ces-1 Snail represents a functional link between cell cycle progression, cell polarity and apoptosis in the NSM lineage.Genetic model of ces-1 Snail functions in the NSM neuroblast (top), the NSM and the NSM sister cell (bottom). In the NSM neuroblast, ces-1 function is negatively regulated by the genes dnj-11 MIDA1 and ces-2 bZIP. ces-1 affects cell cycle progression in the NSM neuroblast by negatively regulating cdc-25.2 Cdc25. ces-1 also affects the polarity of the NSM neuroblast. However, to date, it is unclear through what mechanism. After the asymmetric division of the NSM neuroblast, the level of ces-1 activity is high in the larger NSM (left) and low in the smaller NSM sister cell (right). The activity of ces-1 in the NSM is sufficient to block the function of hlh-2/3 bHLH, thereby resulting in a level of egl-1 BH3-only activity that is too low to induce apoptosis. Conversely, in the NSM sister cell, the activity of ces-1 is not sufficient to block the function of hlh-2/3, thereby resulting in a level of egl-1 activity that is high enough to induce apoptosis. See text for details and molecular interpretations.
Mentions: CES-1 has previously been shown to cause loss of cell polarity in the NSM neuroblast and to suppress apoptosis in its daughter cells [17], [19]. Through a combination of genetic and cell biological studies, we now show that CES-1 also affects cell cycle progression in the NSM neuroblast (See model, Figure 6). In one and the same cell lineage and within a short period of time (<150 min), CES-1 therefore impacts on at least three processes (cell cycle progression, cell polarity and apoptosis) that are fundamentally important to normal development. We speculate that it is through their ability to impact on these processes in a spatially and temporally coordinated manner that Snail-related transcription factors play a crucial role in normal development and tumorigenesis.

Bottom Line: We now demonstrate that CES-1 also affects cell cycle progression in this lineage.Finally, we provide evidence that dnj-11 MIDA1 not only regulate CES-1 activity in the context of cell polarity and apoptosis but also in the context of cell cycle progression.In mammals, the over-expression of Snail-related genes has been implicated in tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrated Protein Science, Department of Biology II, Ludwig-Maximilians-University, Munich, Planegg-Martinsried, Germany ; Department of Genetics, MCB Graduate Program, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

ABSTRACT
The coordination of cell proliferation and cell fate determination is critical during development but the mechanisms through which this is accomplished are unclear. We present evidence that the Snail-related transcription factor CES-1 of Caenorhabditis elegans coordinates these processes in a specific cell lineage. CES-1 can cause loss of cell polarity in the NSM neuroblast. By repressing the transcription of the BH3-only gene egl-1, CES-1 can also suppress apoptosis in the daughters of the NSM neuroblasts. We now demonstrate that CES-1 also affects cell cycle progression in this lineage. Specifically, we found that CES-1 can repress the transcription of the cdc-25.2 gene, which encodes a Cdc25-like phosphatase, thereby enhancing the block in NSM neuroblast division caused by the partial loss of cya-1, which encodes Cyclin A. Our results indicate that CDC-25.2 and CYA-1 control specific cell divisions and that the over-expression of the ces-1 gene leads to incorrect regulation of this functional 'module'. Finally, we provide evidence that dnj-11 MIDA1 not only regulate CES-1 activity in the context of cell polarity and apoptosis but also in the context of cell cycle progression. In mammals, the over-expression of Snail-related genes has been implicated in tumorigenesis. Our findings support the notion that the oncogenic potential of Snail-related transcription factors lies in their capability to, simultaneously, affect cell cycle progression, cell polarity and apoptosis and, hence, the coordination of cell proliferation and cell fate determination.

Show MeSH
Related in: MedlinePlus