p73 cooperates with Ras in the activation of MAP kinase signaling cascade
Open accessAbstract
The p73 gene is capable of inducing cell cycle arrest, apoptosis, senescence, differentiation and to cooperate with oncogenic Ras in cellular transformation. Ras can be considered as a branch point in signal transduction, where diverse extracellular stimuli converge. The intensity of the mitogen-activated protein kinase (MAPK) cascade activation influences the cellular response to Ras. Despite the fundamental role of p53 in Ras-induced growth arrest and senescence, it remains unclear how the Ras/MEK/ERK pathway induces growth arrest in the absence of p53. We report here that oncogenic Ras stabilizes p73 resulting in p73 accumulation and enhancement of its activity. p73, in turn, induces a sustained activation of the MAP kinase cascade synergizing with oncogenic Ras. We also found that inhibition of p73 function modifies the cellular outcome to Ras activation inhibiting Ras-dependent differentiation. Here, we show for the first time that there is a signaling loop between Ras-dependent MAPK cascade activation and p73 function.
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Network analysis connects oncogenic RAS to several mutated driver genes-KMT2D, PIK3CA, PTEN, and IDH1-that control signaling and metabolic pathways in KRAS-driven cancers.
“Network analysis of the several driver mutation genes, including KMT2D138, PIK3CA139, PTEN140, and IDH1141, that regulate signaling and metabolic pathways in KRAS-driven cancers, connects them to oncogenic RAS (Fig 4c).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [141]
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- Authors
- Fernandez-Garcia, B., Vaqué, J. P., Herreros-Villanueva, M., Marques-Garcia, F., Castrillo, F., Fernandez-Medarde, A., León, J., & Marín, M. C.
- Affiliations
- Universidad de León (ES)
- Universidad de Cantabria (ES)
- Corresponding author
- Marín, M C
- ORCID
- Venue
- Cell Death & Differentiation
- Published
- 2006-04-28
- Volume
- 14
- Issue
- 2
- Pages
- 254-265
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- OpenAlex
- W1986493645
- Cited by
- 25
- References
- 40
- Citations by year
- 2024: 1 · 2021: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2015: 4 · 2014: 1 · 2013: 4 · 2012: 3
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Gredos (University of Salamanca) (submittedVersion, cc-by-nc-nd)
- Hispana (submittedVersion, cc-by-nc-nd)
- Funders
- European Social Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- p73, oncogenic Ras, MAPK signaling, MEK/ERK signaling, protein stabilization, growth arrest, cell differentiation, p53-independent signaling, cell transformation
- MeSH terms
- Animals, Cell Differentiation, Cell Transformation, Neoplastic, DNA-Binding Proteins, Enzyme Activation, Humans, Nuclear Proteins, Protein Binding, Genes, ras, Oncogene Protein p21(ras), Tumor Suppressor Protein p53, MAP Kinase Signaling System, Tumor Suppressor Proteins, HCT116 Cells, Extracellular Signal-Regulated MAP Kinases, Rats
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