Mammalian Cyclin D1/Cdk4 complexes induce cell growth in <i>Drosophila</i>

Datar, Sanjeev A.; Galloni, Mireille; Cruz, Aida de la; Marti, Michelle M.; Edgar, Bruce A.; Frei, C.

doi:10.4161/cc.5.6.2573

Cited by 16 publications

(8 citation statements)

References 27 publications

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“…Bearing in mind the morphology of the cells that accumulated cyclin D1 and only faint, dispersed staining in the cells with SAHF, it may also be hypothesized that sequestration probably serves the special purpose of inactivation of the protein on a cellular route to senescence. However, the phenomenon requires a more in-depth revision, especially in face of the fact that mammalian cyclin D1/Cdk4 complexes have been proven to contribute to endoreduplication, most probably via the stimulation of nucleoli enlargement and ribosomal biogenesis [59]. In our study the nuclei of polyploid cells showed often intense cyclin D1 staining, sometimes accompanied by intranucleolar aggregations as well.…”

Section: Discussionmentioning

confidence: 58%

Low-dose etoposide-treatment induces endoreplication and cell death accompanied by cytoskeletal alterations in A549 cells: Does the response involve senescence? The possible role of vimentin

et al. 2013

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BackgroundSenescence in the population of cells is often described as a program of restricted proliferative capacity, which is manifested by broad morphological and biochemical changes including a metabolic shift towards an autophagic-like response and a genotoxic-stress related induction of polyploidy. Concomitantly, the cell cycle progression of a senescent cell is believed to be irreversibly arrested. Recent reports suggest that this phenomenon may have an influence on the therapeutic outcome of anticancer treatment. The aim of this study was to verify the possible involvement of this program in the response to the treatment of the A549 cell population with low doses of etoposide, as well as to describe accompanying cytoskeletal alterations.MethodsAfter treatment with etoposide, selected biochemical and morphological parameters were examined, including: the activity of senescence-associated ß-galactosidase, SAHF formation, cell cycle progression, the induction of p21Cip1/Waf1/Sdi1 and cyclin D1, DNA strand breaks, the disruption of cell membrane asymmetry/integrity and ultrastructural alterations. Vimentin and G-actin cytoskeleton was evaluated both cytometrically and microscopically.Results and conclusionsEtoposide induced a senescence-like phenotype in the population of A549 cells. Morphological alterations were nevertheless not directly coupled with other senescence markers including a stable cell cycle arrest, SAHF formation or p21Cip1/Waf1/Sdi1 induction. Instead, a polyploid, TUNEL-positive fraction of cells visibly grew in number. Also upregulation of cyclin D1 was observed. Here we present preliminary evidence, based on microscopic analyses, that suggest a possible role of vimentin in nuclear alterations accompanying polyploidization-depolyploidization events following genotoxic insults.

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Section: Discussionmentioning

confidence: 58%

Low-dose etoposide-treatment induces endoreplication and cell death accompanied by cytoskeletal alterations in A549 cells: Does the response involve senescence? The possible role of vimentin

et al. 2013

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“…Importantly for this study, overgrowth induced by ectopic expression of Cyclin D/Cdk4 is insensitive to nutrient conditions [49], demonstrating that the Cyclin D/Cdk4 pathway is nutrient-responsive. We now show that ectopic expression of Cyclin D/Cdk4 in the larval fat body is sufficient to drive mitochondrial abundance in a Delg-dependent manner (Fig.…”

Section: Discussionmentioning

confidence: 67%

Nutrition Controls Mitochondrial Biogenesis in the Drosophila Adipose Tissue through Delg and Cyclin D/Cdk4

et al. 2009

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Mitochondria are cellular organelles that perform critical metabolic functions: they generate energy from nutrients but also provide metabolites for de novo synthesis of fatty acids and several amino acids. Thus mitochondrial mass and activity must be coordinated with nutrient availability, yet this remains poorly understood. Here, we demonstrate that Drosophila larvae grown in low yeast food have strong defects in mitochondrial abundance and respiration activity in the larval fat body. This correlates with reduced expression of genes encoding mitochondrial proteins, particularly genes involved in oxidative phosphorylation. Second, genes involved in glutamine metabolism are also expressed in a nutrient-dependent manner, suggesting a coordination of amino acid synthesis with mitochondrial abundance and activity. Moreover, we show that Delg (CG6338), the Drosophila homologue to the alpha subunit of mammalian transcription factor NRF-2/GABP, is required for proper expression of most genes encoding mitochondrial proteins. Our data demonstrate that Delg is critical to adjust mitochondrial abundance in respect to Cyclin D/Cdk4, a growth-promoting complex and glutamine metabolism according to nutrient availability. However, in contrast to nutrients, Delg is not involved in the regulation of mitochondrial activity in the fat body. These findings are the first genetic evidence that the regulation of mitochondrial mass can be uncoupled from mitochondrial activity.

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“…This model is attractive because early activation of cdk2 might cause premature phosphorylation of its substrates and force the G 1 -S phase transition to occur before its time. As cyclin D-cdk4 activity has also been linked to growth control, at least in Drosophila, 45,46 activation of those substrates might also be required to ensure that the smaller G 0 arrested cell is physically ready to enter the cell cycle.…”

confidence: 99%

Switching cyclin D-Cdk4 kinase activity on and off

2008

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The cyclin-cdks are master regulators of cell proliferation. These serine/threonine kinases are the motors that both start and stop the cell cycle in response to proliferative or antiproliferative signals. They phosphorylate substrates required to trigger orderly cell cycle progression, and thus their activity is tightly regulated in order to prevent inappropriate activation. One of the main interfaces between the extraceullar environment and the cell cycle machinery is the interaction of the cyclin-cdks with two families of stoichiometric cyclin kinase inhibitors (CKIs), the Ink4s and the Cip/Kips. As their name suggests, the CKIs have historically been considered negative regulators of the cyclin-cdks, responsible for rapidly and effectively turning off cyclin-cdk activity. However, the interaction of cyclin D-cdk4 with the Cip/Kip family, and with p27Kip1 in particular, appeared complex. In addition to its ability to inhibit cyclin D-cdk4, p27 appeared to be a required assembly factor for the complex, binding in a non-inhibitory mode at least some of the time. Whether p27 was a cyclin D-cdk4/6 inhibitor or not was controversial, and how it might switch between these two modes was unknown. Arguing for a two state mechanism, we have recently shown that p27 can be both a cdk4 bound-inhibitor and a bound-non-inhibitor, depending on the growth state of the cell. This perspective highlights the significance of this finding in terms of normal cell cycle progression and tumor development.

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Mammalian Cyclin D1/Cdk4 complexes induce cell growth in Drosophila

Cited by 16 publications

References 27 publications

Low-dose etoposide-treatment induces endoreplication and cell death accompanied by cytoskeletal alterations in A549 cells: Does the response involve senescence? The possible role of vimentin

Low-dose etoposide-treatment induces endoreplication and cell death accompanied by cytoskeletal alterations in A549 cells: Does the response involve senescence? The possible role of vimentin

Nutrition Controls Mitochondrial Biogenesis in the Drosophila Adipose Tissue through Delg and Cyclin D/Cdk4

Switching cyclin D-Cdk4 kinase activity on and off

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