Cdk4 and Cdk6 Couple the Cell-Cycle Machinery to Cell Growth via mTORC1

Romero-Pozuelo, Jesús; Figlia, Gianluca; Kaya, Oğuzhan; Martín-Villalba, Ana; Teleman, Aurelio A.

doi:10.1016/j.celrep.2020.03.068

Cited by 100 publications

(76 citation statements)

References 49 publications

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“…Despite the direct interaction between cyclin D1 and TSC2 [55], the first to show a direct phosphorylation of TSC2 by CDK4 or CDK6 were Romero-Pozuelo et al in Drosophila [56]. Recently, they also found that cyclin D-CDK4/6 activates mTORC1 by binding and phosphorylation of TSC2 in multiple human and mouse cell lines and pharmacological inhibition of CDK4/6 leads to a rapid, TSC2-dependent reduction of mTORC1 activity [57]. In addition to these findings, another connection between CDK4 and mTORC1 activation was revealed.…”

Section: Amino Acids and Nucleotide Metabolismmentioning

confidence: 99%

The multifaceted role of cell cycle regulators in the coordination of growth and metabolism

et al. 2020

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Adapting to changes in nutrient availability and environmental conditions is a fundamental property of cells. This adaptation requires a multi-directional coordination between metabolism, growth, and the cell cycle regulators (consisting of the family of cyclin-dependent kinases (CDKs), their regulatory subunits known as cyclins, CDK inhibitors, the retinoblastoma family members, and the E2F transcription factors). Deciphering the mechanisms accountable for this coordination is crucial for understanding various patho-physiological processes. While it is well established that metabolism and growth affect cell division, this review will focus on recent observations that demonstrate how cell cycle regulators coordinate metabolism, cell cycle progression, and growth. We will discuss how the cell cycle regulators directly regulate metabolic enzymes and pathways and summarize their involvement in the endolysosomal pathway and in the functions and dynamics of mitochondria.

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Section: Amino Acids and Nucleotide Metabolismmentioning

confidence: 99%

The multifaceted role of cell cycle regulators in the coordination of growth and metabolism

et al. 2020

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“…The role of the CDK4/cyclin D-Rb axis on cell size regulation has been purported by studies from our lab and others (Ginzberg et al, 2018;Schmoller et al, 2015;. While the mechanisms by which CDK4 activity sets target size remains to be investigated, there is increasing evidence that inhibition of CDK4 activity results in increased biosynthetic capacity, such as mitochondrial size and activity, presumably through its feedback on mTORC1 signaling (Cretella et al, 2018;Franco et al, 2016;Haines et al, 2018;Jansen et al, 2017;Romero-Pozuelo et al, 2020).…”

Section: Discussionmentioning

confidence: 91%

Cell size homeostasis is maintained by a circuitry involving a CDK4-determined target size that programs the cell size-dependent activation of p38

Auld

Jenkins

Concannon

2020

Preprint

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While molecules that promote the growth of animal cells have been identified, the following question remains: How are growth promoting pathways regulated to specify a characteristic size for each of the different cell types? In 1975, Hartwell and Nurse suggested that in eukaryotes, cell size is determined by size checkpoints - mechanisms that restrict cell cycle progression from cells that are smaller than their target size. Curiously, such checkpoint mechanisms imply a conceptual distinction between a cell's actual size and cell's target size. In the present study, we materialize this conceptual distinction by describing experimental assays that discriminately quantify a cell's target size value. With these assays, we show that a cell's size and target size are distinct phenotypes that are subject to different upstream regulators. While mTORC1 promotes growth in cell size, our data suggests that a cell's target size value is regulated by other pathways including FGFR3, ROCK2, and CDK4. For example, while rapamycin (an mTORC1 inhibitor) decreases cell size, rapamycin does not change the target size that is required for the G1/S transition. The CDK4/Rb pathway has been previously proposed as a putative regulator of target size. Yet, in lacking experimental means that discriminate perturbations of cell growth from perturbations that reprogram target size, such claims on target size were not validated. To investigate the functions of CDK4 in target size determination, we used genetic and chemical means to 'dial' higher and lower levels of CDK4 activity. These measurements identified functions of CDK4 on target size that are distinct from other G1 CDKs. Using C. elegans, we further demonstrate that these influences of CDK4 on size determination function in vivo. Finally, we propose a model whereby mTORC1, p38, and CDK4 cooperate in a manner that is analogous to the function of a thermostat. While mTORC1 promotes cellular growth as prompted by p38, CDK4 is analogous to the thermostat dial that sets the critical target size associated with cell size homeostasis.

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“…There is evidence that growth information can be integrated by Rb phosphorylation, as Rb inhibition has been shown to result in smaller cell size [138][139][140] and its overexpression, a larger cell size [141]. Recent work has proposed a link between CDK4/6 activity and mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cell growth [142]. The mTOR protein kinase is a key part of a signalling network integrating environmental inputs such as amino acid and oxygen levels, with mTOR activity promoting protein, lipid and nucleotide synthesis and inhibiting autophagy [143].…”

Section: Cell Growth/sizementioning

confidence: 99%

“…The mTOR protein kinase is a key part of a signalling network integrating environmental inputs such as amino acid and oxygen levels, with mTOR activity promoting protein, lipid and nucleotide synthesis and inhibiting autophagy [143]. In addition to Rb phosphorylation, CDK4/6 may also promote mTor activity [142]. In this way, CDK4/6 could couple the cell cycle machinery and cell growth.…”

Section: Cell Growth/sizementioning

confidence: 99%

Restriction point regulation at the crossroads between quiescence and cell proliferation

Pennycook

Barr

2020

FEBS Letters

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The coordination of cell proliferation with reversible cell cycle exit into quiescence is crucial for the development of multicellular organisms and for tissue homeostasis in the adult. The decision between quiescence and proliferation occurs at the restriction point, which is widely thought to be located in the G1 phase of the cell cycle, when cells integrate accumulated extracellular and intracellular signals to drive this binary cellular decision. On the molecular level, decision‐making is exerted through the activation of cyclin‐dependent kinases (CDKs). CDKs phosphorylate the retinoblastoma (Rb) transcriptional repressor to regulate the expression of cell cycle genes. Recently, the classical view of restriction point regulation has been challenged. Here, we review the latest findings on the activation of CDKs, Rb phosphorylation and the nature and position of the restriction point within the cell cycle.

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Cdk4 and Cdk6 Couple the Cell-Cycle Machinery to Cell Growth via mTORC1

Abstract: Highlights d Cdk4/6 regulates mTORC1 activity via TSC2 d Cdk4/6 binds TSC2 and phosphorylates it on Ser1452 and Ser1217 d Cdk4/6 inhibitors also inhibit mTORC1 d Cdk4/6 couples cell-cycle progression via RB to cell growth via mTORC1

Cited by 100 publications

References 49 publications

The multifaceted role of cell cycle regulators in the coordination of growth and metabolism

The multifaceted role of cell cycle regulators in the coordination of growth and metabolism

Cell size homeostasis is maintained by a circuitry involving a CDK4-determined target size that programs the cell size-dependent activation of p38

Restriction point regulation at the crossroads between quiescence and cell proliferation

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