Ral activation promotes melanomagenesis

P. A. Zipfel, D. C. Brady, D. F. Kashatus, B. D. Ancrile, Douglas Tyler, C. M. Counter

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Up to one-third of human melanomas are characterized by an oncogenic mutation in the gene encoding the small guanosine triphosphatase (GTPase) NRAS. Ras proteins activate three primary classes of effectors, namely, Rafs, phosphatidyl-inositol-3-kinases (PI3Ks) and Ral guanine exchange factors (RalGEFs). In melanomas lacking NRAS mutations, the first two effectors can still be activated through an oncogenic BRAF mutation coupled with a loss of the PI3K negative regulator PTEN. This suggests that Ras effectors promote melanoma, regardless of whether they are activated by oncogenic NRas. The only major Ras effector pathway not explored for its role in melanoma is the RalGEF-Ral pathway, in which Ras activation of RalGEFs converts the small GTPases RalA and RalB to an active guanosine triphosphate-bound state. We report that RalA is activated in several human melanoma cancer cell lines harboring an oncogenic NRAS allele, an oncogenic BRAF allele or wild-type NRAS and BRAF alleles. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of RalA, and to a lesser extent of RalB, variably inhibited the tumorigenic growth of melanoma cell lines having these three genotypes. Thus, as is the case for Raf and PI3 K signaling, Rals also contribute to melanoma tumorigenesis.

Original languageEnglish (US)
Pages (from-to)4859-4864
Number of pages6
JournalOncogene
Volume29
Issue number34
DOIs
StatePublished - Aug 26 2010
Externally publishedYes

Fingerprint

Melanoma
Guanine
Alleles
Phosphatidylinositols
Mutation
Phosphotransferases
ras Proteins
Cell Line
Monomeric GTP-Binding Proteins
Guanosine
Guanosine Triphosphate
Small Interfering RNA
Carcinogenesis
Genotype
Growth
Genes
Neoplasms

Keywords

  • melanoma
  • NRas
  • RalA
  • RalB

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

Zipfel, P. A., Brady, D. C., Kashatus, D. F., Ancrile, B. D., Tyler, D., & Counter, C. M. (2010). Ral activation promotes melanomagenesis. Oncogene, 29(34), 4859-4864. https://doi.org/10.1038/onc.2010.224

Ral activation promotes melanomagenesis. / Zipfel, P. A.; Brady, D. C.; Kashatus, D. F.; Ancrile, B. D.; Tyler, Douglas; Counter, C. M.

In: Oncogene, Vol. 29, No. 34, 26.08.2010, p. 4859-4864.

Research output: Contribution to journalArticle

Zipfel, PA, Brady, DC, Kashatus, DF, Ancrile, BD, Tyler, D & Counter, CM 2010, 'Ral activation promotes melanomagenesis', Oncogene, vol. 29, no. 34, pp. 4859-4864. https://doi.org/10.1038/onc.2010.224
Zipfel PA, Brady DC, Kashatus DF, Ancrile BD, Tyler D, Counter CM. Ral activation promotes melanomagenesis. Oncogene. 2010 Aug 26;29(34):4859-4864. https://doi.org/10.1038/onc.2010.224
Zipfel, P. A. ; Brady, D. C. ; Kashatus, D. F. ; Ancrile, B. D. ; Tyler, Douglas ; Counter, C. M. / Ral activation promotes melanomagenesis. In: Oncogene. 2010 ; Vol. 29, No. 34. pp. 4859-4864.
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