The Krüppel-like factor Cabut has cell cycle regulatory properties similar to E2F1

Abstract

Using a gain-of-function screen in Drosophila, we identified the Krüppel-like factor Cabut (Cbt) as a positive regulator of cell cycle gene expression and cell proliferation. Enforced cbt expression is sufficient to induce an extra cell division in the differentiating fly wing or eye, and also promotes intestinal stem cell divisions in the adult gut. Although inappropriate cell proliferation also results from forced expression of the E2f1 transcription factor or its target, Cyclin E, Cbt does not increase E2F1 or Cyclin E activity. Instead, Cbt regulates a large set of E2F1 target genes independently of E2F1, and our data suggest that Cbt acts via distinct binding sites in target gene promoters. Although Cbt was not required for cell proliferation during wing or eye development, Cbt is required for normal intestinal stem cell divisions in the midgut, which expresses E2F1 at relatively low levels. The E2F1-like functions of Cbt identify a distinct mechanism for cell cycle regulation that may be important in certain normal cell cycles, or in cells that cycle inappropriately, such as cancer cells.

The Yun/Prohibitin complex regulates adult Drosophila intestinal stem cell proliferation through the transcription factor E2F1

“…Consistent with a previous report, progenitors are normally arrested in either G1 or G2 phase under physiological conditions ( Fig. 6 A ) ( 47 ). However, depletion of yun/Phb increased the fraction of progenitors in G1 and decreased the fraction in S and G2 phases, indicating that the Yun/PHB complex may regulate cell cycle progression in progenitors ( Fig.…”

“…6 C and SI Appendix , Fig. S35 C ) ( 25 , 47 ). Overexpression of E2F1/Dp in yun/Phb -depleted progenitors significantly rescued the proliferation defects observed in yun/Phb -depleted intestines, respectively, with esg ts > E2F1, yun/Phb RNAi intestines resembling esg ts > E2F1 intestines ( Fig.…”

Influences of repeated exposure to low levels of TiO2 nanoparticles on Kruppel‐like factors in 3D Caco‐2 spheroids and mouse intestines

“…Kruppel‐like factors (KLFs) are a set of transcription factors (TFs) involved in the regulation of many basic biological processes such as stem cell biology, cancer biology, and vascular biology (Cao, 2022b; García‐Niño & Zazueta, 2021; Oishi & Manabe, 2018). In intestines, recent studies revealed that KLFs may be involved in intestinal regeneration (Chen et al, 2020) and maintenance of normal function of intestinal stem cells (Wu et al, 2018; Wu, Sun, et al, 2021; Zhang et al, 2021), indicating that KLFs are crucial regulators for gut biology. Interestingly, recent studies showed that NPs even at non‐cytotoxic concentrations could modulate the expression of KLFs in different models.…”

Cell-cycle exit and stem cell differentiation are coupled through regulation of mitochondrial activity in the Drosophila testis

“…Thus, other factors are capable of controlling expression of the genes required for DNA replication, at least partly redundantly with the E2f complex. Several transcription factors have been described which have overlapping targets with E2f/Dp, including DREF and, recently, the SP/Krüppel-like factor Cabut (Cbt) ( Tue et al., 2017 ; Zhang et al., 2021 ). Intriguingly, Cbt can drive PCNA expression, consistent with our observation that PCNA-GFP is reduced but not absent upon Dp loss of function ( Figures 2 E and S1 D–S1F).…”

“…Thus, continued proliferation and expression of replication genes in the absence of E2f1/Dp could be due either to de-repression from a lack of E2f repressive activity, or to active regulation by other factors such as Cbt. Nonetheless, since Cbt does not drive CycE expression ( Zhang et al., 2021 ), it seems likely that a combination of regulators of replication genes together with specific regulators of CycE are required to promote cell-cycle entry and progression in CySCs.…”