Pointed and Tramtrack69 establish an EGFR-dependent transcriptional switch to regulate mitosis

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.

A Conserved Role But Different Partners for the Transcriptional Corepressor CoREST in Fly and Mammalian Nervous System Formation

“…We were unable to test whether removal of Ttk resulted in coordinate derepression of the neuronal clusters in flies because most of the embryos homozygous for severe ttk alleles (Giesen et al, 1997) died before nervous system formation, similar to the situation in REST knock-out mice. With respect to gain-of-function experiments, overexpression of Ttk early in eye disc development and in sensory organ precursors suppresses the formation of photoreceptors and peripheral sensory neurons, respectively (Guo et al, 1995;Baonza et al, 2002). However, our results, taken together with previous studies (Ramaekers et al, 1997;Paquette et al, 2000;Badenhorst, 2001;Ballas et al, 2001), suggest that developmental context is a critical factor in determining the outcome of gain-of-function or loss-of-function manipulations of REST or Ttk88 in vivo (Armisen et al, 2002).…”

“…Neither protein is expressed in neurons (Harrison and Travers, 1990), but both proteins can block neuronal development (Guo et al, 1995;Giesen et al, 1997;Baonza et al, 2002). In addition, Ttk69 but not Ttk88 expression can arrest cells in the G 2 stage of the cell cycle (Baonza et al, 2002).…”

“…Neither protein is expressed in neurons (Harrison and Travers, 1990), but both proteins can block neuronal development (Guo et al, 1995;Giesen et al, 1997;Baonza et al, 2002). In addition, Ttk69 but not Ttk88 expression can arrest cells in the G 2 stage of the cell cycle (Baonza et al, 2002). Ttk69 can recruit both the NuRD (nucleosome remodeling deacetylase) and the CtBP (Cterminus-binding protein) corepressors (Wen et al, 2000;Murawsky et al, 2001) and has the capacity to form homotetramers through the N-terminal BTB domain it shares with Ttk88 (Badenhorst et al, 2002).…”

Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

“…We searched the dm locus for binding sites of Scalloped (Sd), Stat and Pnt, transcription factors of Hpo, JAK-STAT and EGFR pathways, respectively [27][28][29]. Several potential binding sites for each of these transcription factors were found to be located in a ~1.0 kb region that comprises the first exon and part of the first intron ( Figure 5A).…”

Ectopic Antenna Induction by Overexpression of <i>CG17836/Xrp1</i> Encoding an AT-Hook DNA Binding Motif Protein in <i>Drosophila</i>

“…5) Just behind the MF, however, cells synchronously divide one more time (the second mitotic wave) to produce neuronal cells (R1, R6, R7) and a complement of non-neuronal cells in response to signals from the differentiating cells. [6][7][8][9] The homeodomain-encoding gene cut is turned on in the anterior part of the disc (also called the antennal field) where ey/toy expression is repressed at the second-instar larval stage.…”