Ras signaling in tumor necrosis factor-induced apoptosis.

Trent, Jonathan C.; McConkey, David J.; Loughlin, Susan M.; Harbison, Matthew T.; Fernández, Ariel; Ananthaswamy, Honnavara N.

doi:10.1002/j.1460-2075.1996.tb00827.x

Cited by 80 publications

(72 citation statements)

References 35 publications

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“…Analysis of DNA fragmentation was performed as previously described (Trent et al, 1996) with minor modi®cations. Brie¯y, the cells were harvested and washed twice with PBS.…”

Section: Analysis Of Dna Fragmentationmentioning

confidence: 99%

TGF-β1 actions on FRTL-5 cells provide a model for the physiological regulation of thyroid growth

et al. 1998

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Little is known about the TGF-b1 mechanism that promotes thyroid cell growth arrest. We assessed TGFb1 e ects on Fisher rat thyroid cell line . This allowed us to study TGF-b1 action on thyroid cells in various physiological situations such as actively proliferating cells, resting cells stimulated to proliferate by the action of various mitogens, and resting cells. TGF-b1 arrested proliferating FRTL-5 cells, increasing c-myc mRNA levels and reducing p27-free cyclin D1 protein levels, without a ecting either the cellular content of p27 or the cyclin D1-p27 complexes. Moreover, TGF-b1 treatment reduced the activity of cyclin E-CDK2 complexes and, consequently, pRB was found to be hypophosphorylated. TGF-b1 prevented resting cells to enter in the cell cycle when stimulated with growing medium (newborn calf serum plus a mixture of ®ve hormones) but not when TSH (thyroid stimulating hormone) plus IGF-1 (Insulin-like growth factor I) were used as mitogens. Both stimuli increased the levels of cyclins D1, D3 and E but TGF-b1 had a greater e ect in decreasing these cyclin levels in growing-medium stimulated cells than in TSH+IGF-1. This suggests that for FRTL-5 cells, the content of these cyclins must exceed a threshold to progress through the cell cycle. TGF-b1 induced apoptosis in quiescent cells, accompanied by a reduction in p27 protein levels and an increase in c-myc expression. Interestingly, TGF-b1-induced variations in prothymosin alpha and c-myc mRNA levels were not correlated. TGF-b1 always promoted an increase of p15 mRNA levels. In summary, our results point to the fact that TGF-b1 could play a physiological role in the control of thyroid growth through the modi®cation of cell cycle regulatory proteins.

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“…Analysis of DNA fragmentation was performed as previously described (Trent et al, 1996) with minor modi®cations. Brie¯y, the cells were harvested and washed twice with PBS.…”

Section: Analysis Of Dna Fragmentationmentioning

confidence: 99%

TGF-β1 actions on FRTL-5 cells provide a model for the physiological regulation of thyroid growth

et al. 1998

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“…They are also important components of signaling pathways that regulate cell death (Trent et al, 1996;Kinoshita et al, 1995), cell shape and cell motility (Kundra et al, 1995;Khosravi-Far et al, 1998). The ability of Ras proteins to serve as regulators of signal transduction is conferred on them by structural elements that promote reversible activation (exchange of GDP for GTP) and inactivation (GTP hydrolysis), and by additional structural elements that promote interaction with e ector molecules and association with the cell membrane (Boguski and McCormick, 1993;Cox and Der, 1997;Marshall, 1996;Sche zek et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

A new functional Ras antagonist inhibits human pancreatic tumor growth in nude mice

et al. 1999

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Constitutively active Ras proteins, their regulatory components, and overexpressed tyrosine kinase receptors that activate Ras, are frequently associated with cell transformation in human tumors. This suggests that functional Ras antagonists may have anti-tumor activity. Studies in rodent ®broblasts have shown that S-trans, transfarnesylthiosalicylic acid (FTS) acts as a rather speci®c nontoxic Ras antagonist, dislodging Ras from its membrane anchorage domains and accelerating its degradation. FTS is not a farnesyltransferase inhibitor, and does not a ect Ras maturation. Here we demonstrate that FTS also acts as a functional Ras antagonist in human pancreatic cell lines that express activated KRas (Panc-1 and MiaPaCa-2). In Panc-1 cells, FTS at a concentration of 25 ± 100 mM reduced the amount of Ras in a dose-dependent manner and interfered with serumdependent and epidermal growth factor-stimulated ERK activation, thus inhibiting both anchorage-dependent and anchorage-independent growth of Panc-1 cells in vitro. FTS also inhibited tumor growth in Panc-1 xenografted nude mice, apparently without systemic toxicity. Daily FTS treatment (5 mg/kg intraperitoneally) in mice with tumors (mean volume 0.07 cm 3 ) markedly decreased tumor growth (after treatment for 18 days, tumor volume had increased by only 23+30-fold in the FTStreated group and by 127+66-fold in controls). These ®ndings suggest that FTS represents a new class of functional Ras antagonists with potential therapeutic value.

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“…Primary functions of Ras family members are to control cell growth, di erentiation, transformation and apoptosis (Bollag and McCormick, 1991;Lowy and Willumsen, 1993;Lin et al, 1995;Wang et al, 1995;Trent et al, 1996), whereas those of Rho family members are to regulate organization of the actin cytoskeleton (Hall, 1994;Takai et al, 1995;Narumiya, 1996). Typically, microinjection of RhoA, Rac1 and Cdc42 into cultured ®broblasts induces the actin stress ®bers, membrane ru es (lamellipodia), and microspikes (®lopodia), respectively, as well as the focal complexes associated with these structures Nishiyama et al, 1994;Kozma et al, 1995;Nobes and Hall, 1995).…”

Section: Introductionmentioning

confidence: 99%