Oncogenic Ras activates c-Jun via a separate pathway from the activation of extracellular signal-regulated kinases.

Westwick, John; Cox, Adrienne D.; Der, Channing J.; Cobb, Melanie H.; Hibi, Masahiko; Karin, Michael; Brenner, David A.

doi:10.1073/pnas.91.13.6030

Cited by 175 publications

(150 citation statements)

References 47 publications

Supporting

Mentioning

146

Contrasting

Order By: Relevance

“…Blocking AP1 activity using dominant negative cJun or cFos mutants reverts the transformed phenotype of Ras-overexpressed NIH3T3 ®broblasts (Lloyd et al, 1991;Suzuki et al, 1994). A correlation was also observed between Ras transforming e ciency and cJun transcriptional activity (Alani et al, 1991;Westwick et al, 1994). This is consistent with the idea that AP1 complexes containing cJun are essential downstream e ectors of Ras.…”

Section: Introductionsupporting

confidence: 87%

Transformation by ras modifies AP1 composition and activity

et al. 1997

View full text Add to dashboard Cite

The Ras proteins play a central role in regulating cell growth and their mutation can lead to abnormal proliferation. To analyse the potential link betwen AP1 activity, encoded by members of the jun and fos gene families, and Ras-mediated cellular transformation, we have studied several NIH3T3 clones which overexpress the Ha-Ras or Ki-Ras oncogenes. These transformed ®broblasts accumulated higher levels of cJun, JunB, Fra1 and Fra2 proteins relative to their normal counterparts. They also displayed increased AP1 DNA binding activity which was predominantly composed of cJun and Fra1 containing dimers. Following serum stimulation of Ras clones, the elevated levels of cJun and Fra1 remained steady, while the induction of JunB and Fra2 was partially attenuated. Moreover, deregulated Ras signaling resulted in a complete loss of the serum inducibility of cFos and FosB. Ectopic co-expression of cJun and Fra1 in NIH3T3 ®broblasts led to a transformed phenotype, attenuation of cFos serum inducibility, increased AP1 activity and Cyclin D1 accumulation, all characteristics of oncogenic Ras expressing cells. These results demonstrate that cJun and Fra1 are crucial mediators of the Ras-transformation process.

show abstract

Section: Introductionsupporting

confidence: 87%

Transformation by ras modifies AP1 composition and activity

et al. 1997

View full text Add to dashboard Cite

show abstract

“…Ras proteins play central roles in receptor-mediated signal transduction pathways that control cell proliferation and di erentiation (Khosravi-Far and Der, 1994;Medema and Bos, 1993). Increasing evidence supports the notion that one of the ultimate targets of the ras signaling pathway is the nuclear transcription machinery including the transcription factors c-Jun and Ets, whose activity has been shown to be regulated by oncogenic ras (Westwick et al, 1994;Yang et al, 1996). Therefore, ras plays an essential role in transducing external signals (such as growth factors or other mitogens) to the nucleus.…”

Section: Introductionmentioning

confidence: 92%

K-ras modulates the cell cycle via both positive and negative regulatory pathways

Fan

Bertino

1997

Oncogene

View full text Add to dashboard Cite

“…Ras transformation of rodent ®broblasts can be antagonized by dominant negative mutants of Raf, MEK or MAPK (Kolch et al, 1991;Schaap et al, 1993;Cowley et al, 1994;Westwick et al, 1994;Qiu et al, 1995a;Khosravi-Far et al, 1995), by dominant negative Rho family proteins (Qiu et al, 1995a,b;Prendergast et al, 1995), by blocking the action of speci®c transcription factors (Myc, Fos, Jun, Ets and NFkB) (Sklar et al, 1991;Granger-Schnarr et al, 1992;Langer et al, 1992;Clark et al, 1997d;Finco et al, 1997;Mayo et al, 1997). These observations provoke an apparent paradox.…”

Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 99%

“…S. pombe Ras1 also activates a MAPK cascade (Nishida and Gotoh, 1993). In fact, much of the early clues that identi®ed the positive (CDC25) and negative (IRA) regulators of Ras GDP/GTP cycling came from RAS studies in S. cerevisiae (reviewed in Tamanoi, 1988;Broach, 1991 (Kolch et al, 1991;Schaap et al, 1993;Cowley et al, 1994;Westwick et al, 1994;Qiu et al, 1995a;Khosravi-Far et al, 1995). Similarly, loss of function mutations in Raf, MEK or MAPK homologs disrupt these Rasmediated developmental pathways in¯ies and worms (reviewed in Satoh and Kaziro, 1992).…”

Section: Introductionmentioning

confidence: 99%

Increasing complexity of Ras signaling

et al. 1998

View full text Add to dashboard Cite

The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to de®ne a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was de®ned and conserved in worms,¯ies and man. This was a remarkable achievement in our e orts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identi®cation of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular e ectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple e ectors.

show abstract

Oncogenic Ras activates c-Jun via a separate pathway from the activation of extracellular signal-regulated kinases.

Cited by 175 publications

References 47 publications

Transformation by ras modifies AP1 composition and activity

Transformation by ras modifies AP1 composition and activity

K-ras modulates the cell cycle via both positive and negative regulatory pathways

Increasing complexity of Ras signaling

Contact Info

Product

Resources

About