The coupling of cell growth to the cell cycle

Tapon, Nicolas; Moberg, Kenneth H.; Hariharan, Iswar K.

doi:10.1016/s0955-0674(00)00284-2

Cited by 68 publications

(76 citation statements)

References 62 publications

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“…If the synthesis of cell cycle driving proteins were sensitive to the protein biosynthetic capacity of the cell, then the rate of cell growth could be effectively coupled to cell cycle progression (reviewed in Tapon et al, 2001b). Consistent with this model, the S6K1 and 4E-BP1/ eIF4E pathways function in translational control.…”

Section: Rheb An Activator Of Tor That Is Inhibited By Tsc2mentioning

confidence: 95%

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

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Cell growth (an increase in cell mass and size through macromolecular biosynthesis) and cell cycle progression are generally tightly coupled, allowing cells to proliferate continuously while maintaining their size. The target of rapamycin (TOR) is an evolutionarily conserved kinase that integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryotes) to regulate cell growth and cell cycle progression coordinately. In mammals, TOR is best known to regulate translation through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic translation initiation factor 4E-binding proteins. Consistent with the contribution of translation to growth, TOR regulates cell, organ, and organismal size. The identification of the tumor suppressor proteins tuberous sclerosis1 and 2 (TSC1 and 2) and Ras-homolog enriched in brain (Rheb) has biochemically linked the TOR and phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for the crosstalk that occurs between these pathways. TOR is emerging as a novel antitumor target, since the TOR inhibitor rapamycin appears to be effective against tumors resulting from aberrantly high PI3K signaling. Not only may inhibition of TOR be effective in cancer treatment, but rapamycin is an FDA-approved immunosuppressive and cardiology drug. We review here what is known (and not known) about the function of TOR in cellular and animal physiology.

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Section: Rheb An Activator Of Tor That Is Inhibited By Tsc2mentioning

confidence: 95%

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

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“…In yeast, G 2 /M progression depends on a cell size checkpoint. Although direct coupling of cell size and cell cycle progression is uncertain in mammals (Tapon et al, 2001), the idea is intriguing given that the Golgi apparatus influences cell size via its contribution of membrane to the cell surface. The Golgi itself must double each cell cycle in preparation for cell division.…”

Section: Mek1-mediated Golgi Unlinkingmentioning

confidence: 99%

Mitogen-activated Protein Kinase Kinase 1-dependent Golgi Unlinking Occurs in G₂Phase and Promotes the G₂/M Cell Cycle Transition

Feinstein

Linstedt

2007

MBoC

100

162

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Two controversies have emerged regarding the signaling pathways that regulate Golgi disassembly at the G2/M cell cycle transition. The first controversy concerns the role of mitogen-activated protein kinase activator mitogen-activated protein kinase kinase (MEK)1, and the second controversy concerns the participation of Golgi structure in a novel cell cycle “checkpoint.” A potential simultaneous resolution is suggested by the hypothesis that MEK1 triggers Golgi unlinking in late G2 to control G2/M kinetics. Here, we show that inhibition of MEK1 by RNA interference or by using the MEK1/2-specific inhibitor U0126 delayed the passage of synchronized HeLa cells into M phase. The MEK1 requirement for normal mitotic entry was abrogated if Golgi proteins were dispersed before M phase by treatment of cells with brefeldin A or if GRASP65, which links Golgi stacks into a ribbon network, was depleted. Imaging revealed that unlinking of the Golgi apparatus begins before M phase, is independent of cyclin-dependent kinase 1 activation, and requires MEK signaling. Furthermore, expression of the GRASP family member GRASP55 after alanine substitution of its MEK1-dependent mitotic phosphorylation sites inhibited both late G2 Golgi unlinking and the G2/M transition. Thus, MEK1 plays an in vivo role in Golgi reorganization, which regulates cell cycle progression.

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“…Thus, cell cycle progression is not sufficient to drive cell and organ growth. Conversely, stimulating cell growth alone produces larger organs, but also affects cell size (Johnston and Gallant, 2002;Potter and Xu, 2001;Prober and Edgar, 2001;Stocker and Hafen, 2000;Tapon et al, 2001;Weinkove and Leevers, 2000). For example, artificially stimulating the activities of Ras, Myc or insulin receptor signaling produces more and bigger cells and thus bigger but otherwise normal flies.…”

Section: Regulation Of Cell Proliferation Arrest During Organ Growth mentioning

confidence: 99%

“…Mutations in several genes were isolated that resulted in enlarged heads but did not affect patterning. These include mutations in the Drosophila homologs of PTEN and TSC1/2 tumor suppressor genes, which act in cell growth control pathways that affect cell number as well as cell size (Potter and Xu, 2001;Stocker and Hafen, 2000;Tapon et al, 2001), mutations in warts/lats, a previously described tumor suppressor gene encoding a Ser/Thr kinase (Justice et al, 1995;Xu et al, 1995) that affect cell number but not cell size and mutations in a previously undescribed gene. We named this gene 'shar-pei' because of its folded cuticle phenotype in the head, which resembles the folded skin of Shar-pei dogs.…”

mentioning

confidence: 99%

“…Thus, shrp mutant cells do not accelerate a particular step in the cell cycle. Rather, mutant cells show an even acceleration of cell cycle progression.Manipulating the activity of cell growth regulators such as components of the insulin receptor signaling pathway results in larger organs because of more and larger cells (Johnston and Gallant, 2002;Potter and Xu, 2001;Prober and Edgar, 2001;Stocker and Hafen, 2000;Tapon et al, 2001;Weinkove and Leevers, 2000). To determine whether shrp also affects cell size, we stained mosaic wing discs with antibodies against Dlg to detect apical cell outlines.…”

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confidence: 99%

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Shar-pei mediates cell proliferation arrest during imaginal disc growth inDrosophila

et al. 2002

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During animal development, organ size is determined primarily by the amount of cell proliferation, which must be tightly regulated to ensure the generation of properly proportioned organs. However, little is known about the molecular pathways that direct cells to stop proliferating when an organ has attained its proper size. We have identified mutations in a novel gene, shar-pei, that is required for proper termination of cell proliferation during Drosophila imaginal disc development. Clones of shar-pei mutant cells in imaginal discs produce enlarged tissues containing more cells of normal size. We show that this phenotype is the result of both increased cell proliferation and reduced apoptosis. Hence, shar-pei restricts cell proliferation and promotes apoptosis. By contrast, shar-pei is not required for cell differentiation and pattern formation of adult tissue. Shar-pei is also not required for cell cycle exit during terminal differentiation, indicating that the mechanisms directing cell proliferation arrest during organ growth are distinct from those directing cell cycle exit during terminal differentiation. shar-pei encodes a WW-domain-containing protein that has homologs in worms, mice and humans, suggesting that mechanisms of organ growth control are evolutionarily conserved. and Ripoll, 1975). Notably, after such manipulation of proliferation rates, the final pattern and size of the adult structures are normal. Moreover, discs can regenerate missing parts after surgical manipulation (Bryant, 1978; Bryant and Simpson, 1984) and when ~75% of the progenitor cells of imaginal discs are killed by X-rays, the remaining cells proliferate and compensate for the loss of cells (Haynie and Bryant, 1977). Hence, cell proliferation is plastic and cells in a developing tissue adjust their proliferation depending on whether more cells are needed to build a normal sized structure (Day and Lawrence, 2000;French et al., 1976;Garcia-Bellido and Garcia-Bellido, 1998). However, the molecular mechanisms that direct cells to stop proliferating once the primordium of a structure has reached the correct size are poorly understood.In principle, defined organ size can be generated either by regulating the extent of cell proliferation or by eliminating superfluous cells through programmed cell death, or both. Only limited amounts of cell death are observed during imaginal disc growth (Milan et al., 1997;Wolff and Ready, 1991), indicating that disc size is primarily, albeit not exclusively, controlled at the level of cell division. Thus, factors must exist that regulate the decision of imaginal disc cells to re-enter or exit the cell cycle to mediate growth control.The Drosophila eye is particularly well suited to identify factors that regulate cell proliferation. First, the various stages of cell division and differentiation can be accurately followed in eye imaginal discs. Second, defects in growth control and differentiation can be easily scored. In the early growth phase of the eye disc, cell cycles are not synchronized and pro...

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The coupling of cell growth to the cell cycle

Cited by 68 publications

References 62 publications

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

Mitogen-activated Protein Kinase Kinase 1-dependent Golgi Unlinking Occurs in G₂Phase and Promotes the G₂/M Cell Cycle Transition

Shar-pei mediates cell proliferation arrest during imaginal disc growth inDrosophila

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The coupling of cell growth to the cell cycle

Cited by 68 publications

References 62 publications

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

Mitogen-activated Protein Kinase Kinase 1-dependent Golgi Unlinking Occurs in G2Phase and Promotes the G2/M Cell Cycle Transition

Shar-pei mediates cell proliferation arrest during imaginal disc growth inDrosophila

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Mitogen-activated Protein Kinase Kinase 1-dependent Golgi Unlinking Occurs in G₂Phase and Promotes the G₂/M Cell Cycle Transition