Role of Phosphoinositide 3-OH Kinase in Cell Transformation and Control of the Actin Cytoskeleton by Ras

Rodríguez‐Viciana, Pablo; Warne, Patricia H.; Khwaja, Asim; Marte, Barbara; Pappin, Darryl; Das, Pamela; Waterfield, Michael D.; Ridley, Anne J.; Downward, Julian

doi:10.1016/s0092-8674(00)80226-3

Cited by 994 publications

(932 citation statements)

References 36 publications

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“…Expression of activated Rac1, a downstream e ector of PI3K in the control of membrane ru ing (Rodriguez-Viciana et al, 1997), failed to induce TSH-independent proliferation in FRTL-5 cells. However, similar to reports on ®broblast transformation (Khosravi-Far et al, 1995;Qiu et al, 1995;Rodriguez-Viciana et al, 1997), co-expression of activated forms of Rac1 and MEK1 conferred TSHindependent DNA synthesis, although this e ect was modest compared to that elicited by RasV12 . Together with our data, these results suggest that e ectors in addition to Rac1 are required for PI3K-mediated proliferation in thyroid cells.…”

Section: Discussionsupporting

confidence: 83%

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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Hormones are specialized mitogens that stimulate proliferation in their di erentiated target cells. Thyrotropin (TSH), the physiologic regulator of thyroid cells, stimulates cAMP-mediated proliferation and thyroidspeci®c gene expression. The mitogenic e ects of TSH require Ras, therefore Ras activation should be compatible with the maintenance of thyroid di erentiation. However, expression of activated Ras extinguishes the di erentiated phenotype of thyroid cells. One explanation for this apparent paradox is the selective utilization of Ras e ector pathways. We tested the hypothesis that Ras signaling through PI3K mediates the mitogenic e ects of TSH in cells which retain their di erentiated character. Expression of a Ras e ector mutant (RasV12S35) that signals preferentially through Raf-1, although su cient to confer TSH-independent proliferation, abolished hormone-regulated expression of thyroglobulin and the sodium/iodide symporter. In contrast, expression of a Ras mutant (RasV12C40) that binds selectively to PI3K conferred TSH-independent proliferation without marked e ects on thyroid-speci®c gene expression. Unlike the inhibitory e ects of TSH on the proliferation of RasV12S35-expressing cells, TSH enhanced RasV12C40-stimulated proliferation by further increasing the activity of p70s6k, an important mediator of the mitogenic e ects of TSH and RasV12C40. These results demonstrate that channeling Ras-dependent signals to PI3K confers TSH with the ability to stimulate proliferation in di erentiated cells. Oncogene (2000) 19, 924 ± 932.

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Section: Discussionsupporting

confidence: 83%

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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“…For example, Src may cause activation of PI3K via a Ras-independent mechanism (Liu et al, 1993). However, Ras, but not Src, transformation of NIH3T3 cells, was blocked by inhibition of PI3K (Rodriguez-Viciana et al, 1997). Other Src-mediated pathways that do not involve Ras include induction of Myc (Barone and Courtneidge, 1995) or induction of STAT3 DNA binding activity (Yu et al, 1995).…”

Section: Discussionmentioning

confidence: 98%

“…RalGDS can serve as an exchange factor and activator of the Ras-related proteins RalA and RalB. Ras(12V/40C) can still promote membrane ru ing, activate the JNK pathway (White et al, 1995;Khosravi-Far et al, 1996;Joneson et al, 1996), and may mediate transformation by activation of PI3K (Joneson et al, 1996;Rodriguez-Viciana et al, 1997). To de®ne the Raf-independent pathways that facilitate Ras transformation of RIE-1 cells, it will be important to determine whether constitutive activation of Ral proteins or PI3K alone can cause transformation of RIE-1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…H-Ras (12V/37G) may cause transformation, in part, through interaction with RalGDS , whereas H-Ras(12V/40C) transforming activity has been attributed to activation of PI3K (Joneson et al, 1996;Rodriguez-Viciana et al, 1997). Although HRas(12V/35S) retains the ability to interact with Raf and RalGDS, it is impaired in its interaction with other candidate Ras e ectors (White et al, 1995;KhosraviFar et al, 1996).…”

Section: Farnesyltransferase Inhibitors Impair Ras- But Not Src- Trmentioning

confidence: 99%

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Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade

et al. 1998

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Src transformation of NIH3T3 mouse ®broblasts has been shown to be dependent on Ras function. Since we recently showed that the signaling pathways that mediate Ras transformation of RIE-1 rat intestinal epithelial cells are distinct from those that cause Ras transformation of ®broblasts, we utilized three approaches to determine if Src transformation of RIE-1 cells is dependent on Ras. First, although both Ras and Src cause upregulation of an epidermal growth factor (EGF) receptor-dependent autocrine growth loop, only Ras transformation required this activity. Second, whereas both Src and Ras caused upregulation of the p42 and p44 mitogen-activated protein kinases (MAPKs), only Ras transformation was blocked by the inhibition of MAPK activation by treatment with the PD 98059 MEK inhibitor. Third, treatment with the farnesyltransferase inhibitor FTI-277 blocked Ras, but not Src, transformation. Taken together, these observations suggest that Src transformation of RIE-1 cells is not dependent on Ras. Finally, we determined that Ras activation of Raf-independent pathways alone is su cient to cause growth transformation of RIE-1 cells. Thus, both Ras and Src cause transformation of RIE-1 cells via pathways distinct from those required to cause transformation of NIH3T3 cells.

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“…In addition to their well characterized roles as inducers of cell proliferation, Ras proteins have rapid and profound e ects on the actin cytoskeleton (Nobes and Hall, 1995;Bar-Sagi and Feramisco, 1986;Rodriguez-Viciana et al, 1997). Most importantly, both pathways (i.e.…”

Section: Discussionmentioning

confidence: 99%

Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

et al. 1999

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Prostate cancer cells derived from transgenic mice with adenocarcinoma of the prostate (TRAMP cells) were treated with the HMG-CoA reductase inhibitor, lovastatin. This caused inactivation of the small GTPase RhoA, actin stress ®ber disassembly, cell rounding, growth arrest in the G1 phase of the cell cycle, cell detachment and apoptosis. Addition of geranylgeraniol (GGOL) in the presence of lovastatin, to stimulate protein geranylgeranylation, prevented lovastatin's e ects. That is, RhoA was activated, actin stress ®bers were assembled, the cells assumed a¯at morphology and cell growth resumed. The following observations support an essential role for RhoA in TRAMP cell growth: (1) TRAMP cells expressing dominant-negative RhoA (T19N) mutant protein displayed few actin stress ®bers and grew at a slower rate than controls (35 h doubling time for cells expressing RhoA (T19N) vs 20 h for untransfected cells); (2) TRAMP cells expressing constitutively active RhoA (Q63L) mutant protein displayed a contractile phenotype and grew faster than controls (13 h doubling time). Interestingly, addition of farnesol (FOL) with lovastatin, to stimulate protein farnesylation, prevented lovastatin-induced cell rounding, cell detachment and apoptosis, and stimulated cell spreading to a spindle shaped morphology. However, RhoA remained inactive and growth arrest persisted. The morphological e ects of FOL addition were prevented in TRAMP cells expressing dominant-negative H-Ras (T17N) mutant protein. Thus, it appears that H-Ras is capable of inducing cell spreading, but incapable of supporting cell proliferation, in the absence of geranylgeranylated proteins like RhoA.

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Role of Phosphoinositide 3-OH Kinase in Cell Transformation and Control of the Actin Cytoskeleton by Ras

Cited by 994 publications

References 36 publications

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade

Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

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