RAS and RHO GTPases in G1-phase cell-cycle regulation

Coleman, Mathew L.; Marshall, Christopher J.; Olson, Michael F.

doi:10.1038/nrm1365

Cited by 320 publications

(259 citation statements)

References 130 publications

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“…It also inhibited prolonged activation of ERK and AKT (Figure 6), in remarkable consonance with the loss of function studies reported in Figure 1. Protracted signalling via ERK and AKT couples RTKs to the cell cycle machinery (Vivanco and Sawyers, 2002;Coleman et al, 2004), thus promoting G1 traverse and entrance into S phase. We conclude that loss of RALT signalling complements ERBB2 gene amplification: dramatic overexpression of ErbB-2 promotes its constitutive activation, while removal of RALT is permissive for unabated propagation of ErbB-2 oncogenic signals.…”

Section: Discussionmentioning

confidence: 99%

Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin

Anastasi¹,

et al. 2005

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An emerging paradigm holds that loss of negative signalling to receptor tyrosine kinases (RTKs) is permissive for their oncogenic activity. Herein, we have addressed tumor suppression by RALT/MIG-6, a transcriptionally controlled feedback inhibitor of ErbB RTKs, in breast cancer cells. Knockdown of RALT expression by RNAi enhanced the EGF-dependent proliferation of normal breast epithelial cells, indicating that loss of RALT signalling in breast epithelium may represent an advantageous condition during ErbB-driven tumorigenesis. Although mutational inactivation of the RALT gene was not detected in human breast carcinomas, RALT mRNA and protein expression was strongly and selectively reduced in ERBB2-amplified breast cancer cell lines. Reconstitution of RALT expression in ERBB2-amplified SKBr-3 and BT474 cells inhibited ErbB-2-dependent mitogenic signalling and counteracted the ability of ErbB ligands to promote resistance to the ErbB-2-targeting drug Herceptin. Thus, loss of RALT expression cooperates with ERBB2 gene amplification to drive full oncogenic signalling by the ErbB-2 receptor. Moreover, loss of RALT signalling may adversely affect tumor responses to ErbB-2-targeting agents.

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Section: Discussionmentioning

confidence: 99%

Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin

Anastasi¹,

et al. 2005

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“…Ligation of hormone and growth factor receptors also lead to increased activity of RasGEFs and decreased activity of RasGAPs (e.g. NF1) and subsequently activation of the small GTP-binding protein Ras (Coleman, Marshall, & Olson, 2004). GTP-loaded Ras binds and activates PI3K and/or activates the Raf-MEK-ERK-RSK1 kinase cascade.…”

Section: Regulation Of Mtorc1 By Hormones and Growth Factorsmentioning

confidence: 99%

The TOR signalling network from yeast to man

Virgilio

Loewith

2006

The International Journal of Biochemistry & Cell Biology

208

162

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The target of rapamycin, TOR, is an essential ser/thr protein kinase that functions in two distinct multiprotein complexes, TOR complex 1 and 2. The structure and functions of these complexes have been conserved from yeast to man. TOR complex 1 is inhibited by rapamycin and is thought to couple growth cues to cellular metabolism; TOR complex 2 is not inhibited by rapamycin and appears to regulate spatial aspects of growth such as cell polarity. Work done in a variety of model systems, continues to contribute to our current understanding of this TOR signalling network. Recent studies in flies and mammalian tissue culture cells have elucidated many signalling components upstream of TOR complex 1. These studies also suggest that aberrant mammalian TOR complex 1 signalling contributes to a number of pathologies ranging from metabolic diseases to hyperproliferative disorders and cancers. Consequently the efficacies of rapamycin and related compounds in treating such diseases are being evaluated in clinical trials.

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“…Isoprenoids, such as farnesyl pyrophosphate (FPP) and GGPP, are utilized for prenylating membrane-bound small GTPases, such as members of the Ras superfamily, which play critical roles in cell proliferation and cytoskeletal maintenance (12,13). Isoprenylation of these proteins is necessary for their translocation to the plasma membrane and subsequent activation.…”

mentioning

confidence: 99%

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

Murthy¹,

Tong²,

Hohl

2005

Journal of Biological Chemistry

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Fatty acid biosynthesis is transcriptionally regulated by liver X receptor (LXR) and its gene target, sterol regulatory element binding protein-1c (SREBP-1c). LXR activation is induced by oxysterol end products of the mevalonate pathway and is inhibited by the upstream non-sterol isoprenoid, geranylgeranyl pyrophosphate (GGPP). Whether isoprenoids play a role in regulating the transcription of genes involved in fatty acid biosynthesis is unknown. In CaCo-2 colon epithelial cells, depletion of mevalonate and its derivatives, including oxysterol ligands for LXR, increased fatty acid synthesis. Addition of mevalonate or its isoprenoid derivative, farnesyl pyrophosphate (FPP), prevented this increase. The effects of FPP were likely due to itself or its degradation products, because none of its downstream derivatives, GGPP, ubiquinone, or cholesterol, were effective. Moreover, the effects of FPP could not be accounted for by protein prenylation, because inhibition of farnesylation did not alter fatty acid synthesis in mevalonate-depleted cells incubated with the isoprenoid. Neither was fatty acid synthesis in these cells altered by inhibition of ␤-oxidation. Mevalonate depletion increased fatty acid synthase (FAS) mRNA by transcriptional mechanisms, without increasing gene expression of other enzymes involved in fatty acid biosynthesis or of SREBP-1c. The abundance of mature SREBP-2 but not SREBP-1 was increased following mevalonate depletion. FPP prevented the increase in FAS mRNA in mevalonate-depleted cells without altering SREBP-2 activation. Thus, FPP regulates fatty acid synthesis by a mechanism that is likely independent of the SREBP pathway.The biosynthesis of fatty acids and cholesterol are closely related. Enzymes catalyzing the synthesis and metabolism of both lipids are coordinately regulated by the same transcription factors, the sterol regulatory element-binding proteins (SREBPs) 2 and the liver X receptors (LXRs) (1-3). LXRs belong to a superfamily of nuclear hormone receptors that are ligand-activated transcription factors (3). They form obligate heterodimers with retinoid X receptors (RXRs), another member of this receptor family, and subsequently bind to specific response ele-

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RAS and RHO GTPases in G1-phase cell-cycle regulation

Cited by 320 publications

References 130 publications

Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin

Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin

The TOR signalling network from yeast to man

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

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