The DOI matches its Crossref record; 96 of the 96 references it cites were found in a registry or an index.
High-Intensity Raf Signal Causes Cell Cycle Arrest Mediated by p21 Cip1
Open accessAbstract
Activated Raf has been linked to such opposing cellular responses as the induction of DNA synthesis and the inhibition of proliferation. However, it remains unclear how such a switch in signal specificity is regulated. We have addressed this question with a regulatable Raf-androgen receptor fusion protein in murine fibroblasts. We show that Raf can cause a G1-specific cell cycle arrest through induction of p21Cip1. This in turn leads to inhibition of cyclin D- and cyclin E-dependent kinases and an accumulation of hypophosphorylated Rb. Importantly, this behavior can be observed only in response to a strong Raf signal. In contrast, moderate Raf activity induces DNA synthesis and is sufficient to induce cyclin D expression. Therefore, Raf signal specificity can be determined by modulation of signal strength presumably through the induction of distinct protein expression patterns. Similar to induction of Raf, a strong induction of activated Ras via a tetracycline-dependent promoter also causes inhibition of proliferation and p21Cip1 induction at high expression levels. Thus, p21Cip1 plays a key role in determining cellular responses to Ras and Raf signalling. As predicted by this finding we show that Ras and loss of p21 cooperate to confer a proliferative advantage to mouse embryo fibroblasts.
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Cites
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WAF1, a potential mediator of p53 tumor suppression
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Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
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“p21 Cip1 induction via activation of neuronal growth factor (NGF) receptors, Ras, or Raf followed by growth arrest has recently been observed in several cell types (13, 46, 78, 89) and depends on MEK activity in at least NIH 3T3 (69) and Schwann cells (61a).”
BackgroundMarshall, C. J. (1995) · Cell · doi:10.1016/0092-8674(95)90401-8 · Cited by 3,906
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Self-citationMice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control
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Self-citationWAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.
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Cited by
MAP kinase signalling pathways in cancer
Dhillon, A. S., Hagan, S., Rath, O., & Kolch, W. (2007) · Oncogene · doi:10.1038/sj.onc.1210421 · Cited by 2,995
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Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP
Yeung, K., Seitz, T., Li, S., Janosch, P., McFerran, B., Kaiser, C., Fee, F., Katsanakis, K. D., Rose, D. W., Mischak, H., et al. (1999) · Nature · doi:10.1038/43686 · Cited by 893
Mapk signal specificity: The right place at the right time
Murphy, L. O., & Blenis, J. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.03.009 · Cited by 707
Metadata
- Authors
- Sewing, A., Wiseman, B., Lloyd, A. C., & Land, H.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1997-09
- Volume
- 17
- Issue
- 9
- Pages
- 5588-5597
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2112533411
- Cited by
- 462
- References
- 96
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- green
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