Suppression of Ras-Induced Transformation of NIH 3T3 Cells by Activated Gα
            <sub>S</sub>

Chen, Jianghao; Iyengar, Ravi

doi:10.1126/science.8122111

Cited by 118 publications

(79 citation statements)

References 22 publications

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“…1C). Interestingly, this kinetic profile contrasts with our previous observations in NIH 3T3 cells (16), where cAMP and Rap1b negatively modulate cell growth (38)(39)(40). In these cells, cAMP stimulation of Rap1b shows an initial peak similar to the one described here for thyroid cells, followed by a second wave of sustained activation (16,39).…”

Section: A Physiological Model To Test the Notion That Rap1b Mediatescontrasting

confidence: 54%

On the mitogenic properties of Rap1b: cAMP-induced G ₁ /S entry requires activated and phosphorylated Rap1b

Ribeiro-Neto

Urbani

Lemee

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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We have shown that the small GTPase Rap1b, a protein known to antagonize the mitogenic and transforming activity of Ras, is endowed with both mitogenic and tumorigenic properties. Rap1b can be activated by cAMP, an intracellular message known to either stimulate or inhibit cell proliferation. The oncogenic property of Rap1b was revealed in a model system in which cAMP stimulates cell proliferation and was linked to Rap's ability to promote S phase entry. We have now tested the significance of the mitogenic action of Rap1b in a physiologically relevant model, the differentiated thyroid follicular cells, a system that requires thyroid-stimulating hormone (TSH), acting via cAMP, to mediate a full mitogenic response. Here we report that cAMP-dependent hormonal stimulation of DNA synthesis requires Rap1b in a manner dependent on its phosphorylation by protein kinase A.

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Section: A Physiological Model To Test the Notion That Rap1b Mediatescontrasting

confidence: 54%

On the mitogenic properties of Rap1b: cAMP-induced G ₁ /S entry requires activated and phosphorylated Rap1b

Ribeiro-Neto

Urbani

Lemee

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…We have recently reported that growth of cells, NIH 3T3, normally inhibited by cAMP (Magnaldo et al, 1989;Chen and Iyengar 1994), can be potently stimulated by cAMP if the PKA subunit RIIb is expressed in these cells (Porcellini et al, 2003). The presence of RIIb in these lines amplified cAMP survival and transcriptional signals.…”

Section: Introductionmentioning

confidence: 99%

The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals

et al. 2006

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Phosphatidylinositol 3-kinase (PI3K) is necessary for thyroid stimulating hormone (TSH)-induced cell cycle progression. To determine the molecular mechanism linking PI3K to TSH, we have identified a serine residue in p85a PI3K phosphorylated by protein kinase A (PKA) in vitro and in vivo. Expression of an alanine mutant (p85A) abolished cyclic AMP/TSH-induced cell cycle progression and was lethal in thyroid cells . The aspartic version of the p85a PI3K (p85D) inhibited apoptosis following TSH withdrawal. The p85a PI3K wild type not the p85A bound PKA regulatory subunit RIIb in cells stimulated with cAMP or TSH. The binding of the aspartic version of p85a PI3K to RIIb was independent of cAMP or TSH stimulation. Similarly, binding of PI3K to p21Ras and activation of AKT, a downstream PI3K target, were severely impaired in cells expressing the p85A mutant. Finally, we found that the catalytic activity of PI3K was stimulated by TSH in cells expressing the wildtype p85a PI3K but not in cells expressing p85A. This latter mutant did not affect the epidermal growth factorstimulated PI3K activity. We suggest that (1) TSHcAMP-induced PKA phosphorylates p85a PI3K at serine 83, (2) phosphorylated p85a PI3K binds RIIb-PKA and targets PKAII to the membrane, and (3) PI3K activity and p21Ras binding to PI3K increase and activate PI3K downstream targets. This pathway is essential for the transmission of TSH-cAMP growth signals.

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“…Although the mechanism by which v-Abl activates Ras remains unknown, it has been suggested that v-Abl can interact directly with Shc thereby initiating the formation of a complex with Grb2-mSos and ensuing Ras-Raf activation (49). A mutationally activated form of Ras, most commonly G12V, is found in up to 30% of all human tumors (53)(54)(55)(56)(57)(58)(59)(60)(61).…”

Section: Caveolin-1 Expression Inhibits Ras-mediated Transcriptional mentioning

confidence: 99%

Recombinant Expression of Caveolin-1 in Oncogenically Transformed Cells Abrogates Anchorage-independent Growth

Engelman¹,

Wykoff²,

Yasuhara³

et al. 1997

Journal of Biological Chemistry

345

336

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Caveolae are plasma membrane-attached vesicular organelles. Caveolin-1, a 21-24-kDa integral membrane protein, is a principal component of caveolae membranes in vivo. Both caveolae and caveolin are most abundantly expressed in terminally differentiated cells: adipocytes, endothelial cells, and muscle cells. Conversely, caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes such as v-abl and H-ras (G12V); caveolae are absent from these cell lines. However, its remains unknown whether down-regulation of caveolin-1 protein and caveolae organelles contributes to their transformed phenotype.Here, we have expressed caveolin-1 in oncogenically transformed cells under the control of an inducible-expression system. Regulated induction of caveolin-1 expression was monitored by Western blot analysis and immunofluorescence microscopy. Our results indicate that caveolin-1 protein is expressed well using this system and correctly localizes to the plasma membrane. Induction of caveolin-1 expression in v-Abl-transformed and H-Ras (G12V)-transformed NIH 3T3 cells abrogated the anchorage-independent growth of these cells in soft agar and resulted in the de novo formation of caveolae as seen by transmission electron microscopy. Consistent with its antagonism of Ras-mediated cell transformation, caveolin-1 expression dramatically inhibited both Ras/MAPK-mediated and basal transcriptional activation of a mitogen-sensitive promoter. Using an established system to detect apoptotic cell death, it appears that the effects of caveolin-1 may, in part, be attributed to its ability to initiate apoptosis in rapidly dividing cells. In addition, we find that caveolin-1 expression levels are reversibly down-regulated by two distinct oncogenic stimuli. Taken together, our results indicate that down-regulation of caveolin-1 expression and caveolae organelles may be critical to maintaining the transformed phenotype in certain cell populations.

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Suppression of Ras-Induced Transformation of NIH 3T3 Cells by Activated Gα _S

Cited by 118 publications

References 22 publications

On the mitogenic properties of Rap1b: cAMP-induced G ₁ /S entry requires activated and phosphorylated Rap1b

On the mitogenic properties of Rap1b: cAMP-induced G ₁ /S entry requires activated and phosphorylated Rap1b

The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals

Recombinant Expression of Caveolin-1 in Oncogenically Transformed Cells Abrogates Anchorage-independent Growth

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Suppression of Ras-Induced Transformation of NIH 3T3 Cells by Activated Gα S

Cited by 118 publications

References 22 publications

On the mitogenic properties of Rap1b: cAMP-induced G 1 /S entry requires activated and phosphorylated Rap1b

On the mitogenic properties of Rap1b: cAMP-induced G 1 /S entry requires activated and phosphorylated Rap1b

The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals

Recombinant Expression of Caveolin-1 in Oncogenically Transformed Cells Abrogates Anchorage-independent Growth

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Suppression of Ras-Induced Transformation of NIH 3T3 Cells by Activated Gα _S

On the mitogenic properties of Rap1b: cAMP-induced G ₁ /S entry requires activated and phosphorylated Rap1b

On the mitogenic properties of Rap1b: cAMP-induced G ₁ /S entry requires activated and phosphorylated Rap1b