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Pointed and Tramtrack69 establish an EGFR-dependent transcriptional switch to regulate mitosis
Antonio Baonza1, Christopher M Murawsky, Andrew A Travers
1MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
Abstract:
Cell division in animals must be regulated; during development, for example, proliferation often occurs in spatially and temporally restricted patterns, and loss of mitotic control underlies cancer. The epidermal growth factor receptor (EGFR) has been implicated extensively in the control of cell proliferation in metazoans; in addition, hyperactivity of the EGFR and its three relatives, ErbB2-ErbB4, are implicated in many cancers. But little is known about how these receptor tyrosine kinases regulate the cell cycle. In the developing Drosophila melanogaster imaginal eye disc, there is a single patterned mitosis that sweeps across the eye disc epithelium in the third larval instar. This 'second mitotic wave' is triggered by EGFR signalling and depends on expression of String, the Drosophila homologue of Cdc25 phosphatase, the ultimate regulator of mitosis in all eukaryotic cells. Here we show that two antagonistic transcriptional regulators, Pointed, an activator, and Tramtrack69, a repressor, directly regulate the transcription of string. The activity of at least one of these regulators, Pointed, is controlled by EGFR signalling. This establishes a molecular mechanism for how intercellular signalling can control string expression, and thereby cell proliferation.
Insights
Epidermal growth factor receptor (EGFR) signaling controls cell proliferation by regulating the String gene. This pathway involves Pointed and Tramtrack69 transcriptional regulators, crucial for cell cycle control in Drosophila eye development.
Area of Science:
- Developmental Biology
- Cell Biology
- Molecular Biology
Background:
- Cell division regulation is critical for animal development and preventing cancer.
- Epidermal growth factor receptor (EGFR) signaling pathways are known to control cell proliferation.
- The precise mechanisms by which receptor tyrosine kinases regulate the cell cycle remain largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanism by which EGFR signaling controls cell cycle progression.
- To identify the transcriptional regulators involved in the 'second mitotic wave' during Drosophila eye disc development.
Main Methods:
- Investigated the role of transcriptional regulators Pointed and Tramtrack69 in Drosophila melanogaster.
- Analyzed the regulation of the String gene, a homolog of Cdc25 phosphatase.
- Examined the control of Pointed activity by EGFR signaling.
Main Results:
- Demonstrated that Pointed and Tramtrack69 directly regulate the transcription of the String gene.
- Showed that EGFR signaling controls the activity of the Pointed transcriptional regulator.
- Established a link between intercellular signaling and the regulation of cell proliferation via String expression.
Conclusions:
- EGFR signaling modulates cell proliferation through the transcriptional regulation of String by Pointed and Tramtrack69.
- This study provides a molecular mechanism connecting intercellular communication to cell cycle control.
- Findings offer insights into developmental processes and potential cancer mechanisms related to mitotic control.