ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells

Implications towards sensitization to apoptosis

Mikhail Krasilnikov, Vladimir N. Ivanov, Jianli Dong, Ze'ev Ronai

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Signal transducers and activators of transcription (STAT) proteins nuclear translocation and transcriptional activity are regulated by diverse protein kinases in response to extracellular stimuli by cytokines, growth factors and stress. Using two melanoma-derived cell lines that exhibit marked differences in basal activities of MAPKs and PI3K-AKT, we studied changes both in STAT activities and in their sensitization to apoptosis. Activating mutations of B-RAF (T1796A) and impaired expression of PTEN are detected in LU1205, but not in FEMX melanoma cells, and are reflected in high basal levels of expression and activities of MAPKs and PI3K-AKT. Treatment with either PD98059 (PD) or LY294002 (LY), the pharmacological inhibitors of MEK-ERK and PI3K, respectively, markedly increased GAS-Luc activity in LU1205, but not in FEMX cells. Tyrosine phosphorylation of STAT3/5 and of JAK2 also increased upon treatment of LU1205 cells with either PD or LY, suggesting that constitutive active MAPK and PI3K signals inhibit tyrosine phosphorylation of JAK/STATs. Treatment of FEMX and LU1205 with PD sensitized the cells to apoptosis, albeit by TNFα and TRAIL death cascades, respectively, indicating that additional yet distinct targets are affected by each signaling pathway. Indeed, the combination of LY and PD treatment synergistically increased the apoptosis of LU1205 and FEMX cells. Overall, whereas PI3K and MAPK down-regulate JAK-STAT signaling, additional targets are affected by these kinases and sensitizes melanoma to apoptosis via distinct death cascades.

Original languageEnglish (US)
Pages (from-to)4092-4101
Number of pages10
JournalOncogene
Volume22
Issue number26
DOIs
StatePublished - Jun 26 2003
Externally publishedYes

Fingerprint

Transducers
Phosphatidylinositol 3-Kinases
Human Activities
Melanoma
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Apoptosis
Tyrosine
Phosphorylation
STAT Transcription Factors
Mitogen-Activated Protein Kinase Kinases
Protein Transport
Protein Kinases
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Down-Regulation
Pharmacology
Cytokines
Cell Line
Mutation
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Keywords

  • Apoptosis
  • ERK
  • Melanoma
  • PI3K
  • STAT

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells : Implications towards sensitization to apoptosis. / Krasilnikov, Mikhail; Ivanov, Vladimir N.; Dong, Jianli; Ronai, Ze'ev.

In: Oncogene, Vol. 22, No. 26, 26.06.2003, p. 4092-4101.

Research output: Contribution to journalArticle

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