Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in <i>Drosophila</i>

Sun, Dan; Buttitta, Laura

doi:10.1242/dev.120824

Cited by 19 publications

(21 citation statements)

References 79 publications

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“…These in vivo findings, together with numerous biochemical studies showing that PP2A can dephosphorylate Akt (Perrotti & Neviani, 2013;Seshacharyulu et al, 2013), indicate that a [Ca 2+ ]i-regulated PP2A isoform(s) likely acts downstream of TRPV6/Trpv6 and regulates the quiescent state in epithelial cells. This is in good agreement with a recent study in Drosophila showing that compromising PP2A activity delays cell cycle exit (Sun & Buttitta, 2015). The TRPV6-[Ca 2+ ]i-PP2A-Akt signaling axis appears to be conserved in human colon cells because inhibition of TRPV6, [Ca 2+ ]i and PP2A all increased LoVo cell proliferation.…”

Section: Discussionsupporting

confidence: 91%

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Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

Malick

et al. 2019

Preprint

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Epithelial homeostasis and regeneration require a pool of quiescent cells. How the quiescent cells are established and maintained is poorly understood. Here we report that Trpv6, a cation channel responsible for epithelial Ca 2+ absorption, functions as a key regulator of cellular quiescence. Genetic deletion and pharmacological blockade of Trpv6 promoted zebrafish epithelial cells to exit from quiescence and re-enter the cell cycle. Reintroducing Trpv6, but not its channel dead mutant, restored the quiescent state. Ca 2+ imaging showed that Trpv6 is constitutively open in vivo. Mechanistically, Trpv6-mediated Ca 2+ influx maintained the quiescent state by suppressing insulin-like growth factor (IGF)-mediated Akt and Tor signaling.In zebrafish epithelia and human colon cancer cells, Trpv6/TRPV6 elevated intracellular Ca 2+ levels and activated PP2A, which down-regulated IGF signaling and promoted the quiescent state. Our findings suggest that Trpv6 mediates constitutive Ca 2+ influx into epithelial cells to continuously suppress growth factor signaling and maintain the quiescent state.

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Section: Discussionsupporting

confidence: 91%

“…While non-proliferative, these cells retain the ability to re-enter the cell cycle in response to appropriate cell-intrinsic and extrinsic signals (Matson & Cook, 2017;Sun & Buttitta, 2015;Yao, 2014). Quiescence protects long-lived cells, such as adult stem cells against the accumulation of genomic aberrations and stress.…”

Section: Introductionmentioning

confidence: 99%

Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

Malick

et al. 2019

Preprint

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“…Prolonging the final G2/M effectively delayed cell cycle exit with timing similar to that observed when we compromise NuA4 function (up to 30 hr APF, Figure 7, A and B), while prolonging the final cell cycle with an RNAi to e2f1 or the expression of a dominantly active Rbf, Rbf 280 , did not perturb the overall timing of cell cycle exit ( Figure S7, A-D). Other genetic conditions known to prolong the cell cycle such as generating Minute +/2 clones or slowly dividing Dp null mutant clones also did not detectibly delay cell cycle exit in the pupal wing (Martin and Morata 2006;Sun and Buttitta 2015). This demonstrates that simply slowing cell cycles during the proliferative phases or slowing the final G1/S does not delay cell cycle exit in the wing.…”

Section: Nua4 Inhibition Does Not Delay Cell Cycle Exit Through the Pmentioning

confidence: 88%

Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Flegel¹,

Grushko²,

Bolin³

et al. 2016

Genetics

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Robust and synchronous repression of E2F-dependent gene expression is critical to the proper timing of cell cycle exit when cells transition to a postmitotic state. Previously NuA4 was suggested to act as a barrier to proliferation in Drosophila by repressing E2F-dependent gene expression. Here we show that NuA4 activity is required for proper cell cycle exit and the repression of cell cycle genes during the transition to a postmitotic state in vivo. However, the delay of cell cycle exit caused by compromising NuA4 is not due to additional proliferation or effects on E2F activity. Instead NuA4 inhibition results in slowed cell cycle progression through late S and G2 phases due to aberrant activation of an intrinsic p53-independent DNA damage response. A reduction in NuA4 function ultimately produces a paradoxical cell cycle gene expression program, where certain cell cycle genes become derepressed in cells that are delayed during the G2 phase of the final cell cycle. Bypassing the G2 delay when NuA4 is inhibited leads to abnormal mitoses and results in severe tissue defects. NuA4 physically and genetically interacts with components of the E2F complex termed Drosophila, Rbf, E2F and Myb/Multi-vulva class B (DREAM/MMB), and modulates a DREAM/MMB-dependent ectopic neuron phenotype in the posterior wing margin. However, this effect is also likely due to the cell cycle delay, as simply reducing Cdk1 is sufficient to generate a similar phenotype. Our work reveals that the major requirement for NuA4 in the cell cycle in vivo is to suppress an endogenous DNA damage response, which is required to coordinate proper S and G2 cell cycle progression with differentiation and cell cycle gene expression.KEYWORDS DNA damage; proliferation; H2Av; cell cycle checkpoint; cell cycle exit A conserved eukaryotic transcriptional oscillator controls cell cycle gene expression in proliferating cells and underlies the well-studied Cyclin/Cdk cell cycle protein oscillator (Orlando et al. 2008;Oikonomou and Cross 2010). In metazoans, this oscillator depends upon transcriptional activation of several hundred cell cycle genes, initiated by E2F transcription factor complexes followed by E2F inhibition (or degradation) (Shibutani et al. 2008;Zielke et al. 2011;Sadasivam and Decaprio 2013). This generates an oscillation of chromatin opening and closing at cell cycle genes that is thought to properly coordinate G1/S and G2/M gene expression as well as the transition to a noncycling state (Litovchick et al. 2007(Litovchick et al. , 2011Forristal et al. 2014). Disruption of this coordination can affect cell cycle progression by causing inappropriate gene expression (Reis and Edgar 2004;Wen et al. 2008;Forristal et al. 2014). While the oscillation of E2F activity is required for robust cell cycle gene expression Korenjak et al. 2012), E2F complexes are not absolutely essential for cell cycle progression or timely cell cycle exit in Drosophila (Frolov et al. 2001(Frolov et al. , 2005. In the absence of E2F activity there must be E2F-independ...

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“…Western blots were performed using BioRad TGX precast 4-20% gels, and HRP conjugated secondary antibodies with high sensitivity ECL detection reagents (Thermo) as described (Sun and Buttitta, 2015). We used the following antibodies: anti-Tyr15-P-cdc2 (1:1000, Cell Signaling Technologies, #9111), anti-EcR common (1:1000, DSHB, DDA2.7), anti-Wee (1:700, kindly provided by Dr S. Campbell), anti-Broad Z1 and Broad-Core (1:100, DSHB, #Z1.3C11.OA1 and #25E9.D7), mouse anti-α-tubulin (1:1000, DSHB, AA4.3) and anti-total cdc2 (1:1000, Millipore, #06-923).…”

Section: Methodsmentioning

confidence: 99%

Ecdysone signaling induces two phases of cell cycle exit inDrosophilacells

et al. 2016

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During development, cell proliferation and differentiation must be tightly coordinated to ensure proper tissue morphogenesis. Because steroid hormones are central regulators of developmental timing, understanding the links between steroid hormone signaling and cell proliferation is crucial to understanding the molecular basis of morphogenesis. Here we examined the mechanism by which the steroid hormone ecdysone regulates the cell cycle in Drosophila. We find that a cell cycle arrest induced by ecdysone in Drosophila cell culture is analogous to a G2 cell cycle arrest observed in the early pupa wing. We show that in the wing, ecdysone signaling at the larva-to-puparium transition induces Broad which in turn represses the cdc25c phosphatase String. The repression of String generates a temporary G2 arrest that synchronizes the cell cycle in the wing epithelium during early pupa wing elongation and flattening. As ecdysone levels decline after the larva-to-puparium pulse during early metamorphosis, Broad expression plummets, allowing String to become re-activated, which promotes rapid G2/M progression and a subsequent synchronized final cell cycle in the wing. In this manner, pulses of ecdysone can both synchronize the final cell cycle and promote the coordinated acquisition of terminal differentiation characteristics in the wing.

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Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila

Cited by 19 publications

References 79 publications

Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Ecdysone signaling induces two phases of cell cycle exit inDrosophilacells

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