CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells

Woan Ruoh Lee, Shing Chuan Shen, Pei Ru Wu, Chia Lun Chou, Yi Hsien Shih, Chung Min Yeh, Kun Tu Yeh, Ming Chung Jiang

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The Ras/ERK (extracellular signal-regulated protein kinase) and cAMP/PKA (protein kinase A) pathways are essential for the transcriptional activities of CREB (cAMP response element binding protein) and MITF (microphthalmia-associated transcription factor) in melanogenesis and the progression of melanoma. However, the interaction between Ras/ERK and cAMP/PKA pathways in the melanogenesis and progression of melanoma is not fully known. Here, we report that CSE1L (chromosome segregation 1-like protein) regulates cAMP/PKA-induced CREB and MITF expressions as well as Ras-induced ERK1/2 phosphorylation. IBMX, a cAMP/PKA activator, treatment induced CSE1L phosphorylation and augmented Ras-induced ERK1/2 phosphorylation. CSE1L knockdown by CSE1L shRNA expression vectors inhibited Ras-induced ERK1/2 phosphorylation and melanogenesis in melanoma cells. CSE1L overexpression increased phospho-CREB expression; CSE1L knockdown also inhibited Ras-induced phospho-CREB, MITF, and tyrosinase expressions, regardless of the presence of IBMX. This study identifies CSE1L links and controls the Ras/ERK and cAMP/PKA pathways in the melanogenesis of melanoma cells. Melanomas frequently develop drug resistance via paradoxical activation of Ras/Raf/MEK/ERK or alternatively activated Ras/ERK and cAMP/PKA pathways. Thus CSE1L may be a potential target for treating melanomas that harbor Ras mutations or are resistant to drugs targeting Raf/MEK/ERK.

Original languageEnglish
JournalMolecular Carcinogenesis
DOIs
Publication statusPublished - Nov 2016

Fingerprint

Cellular Apoptosis Susceptibility Protein
Microphthalmia-Associated Transcription Factor
Cyclic AMP Response Element-Binding Protein
MAP Kinase Signaling System
Melanoma
Phosphorylation
1-Methyl-3-isobutylxanthine
Mitogen-Activated Protein Kinase Kinases
Monophenol Monooxygenase
Extracellular Signal-Regulated MAP Kinases
Drug Delivery Systems
Drug Resistance
Protein Kinases
Small Interfering RNA

Keywords

  • CREB
  • CSE1L
  • ERK1/2
  • Melanoma
  • MITF
  • Ras

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells. / Lee, Woan Ruoh; Shen, Shing Chuan; Wu, Pei Ru; Chou, Chia Lun; Shih, Yi Hsien; Yeh, Chung Min; Yeh, Kun Tu; Jiang, Ming Chung.

In: Molecular Carcinogenesis, 11.2016.

Research output: Contribution to journalArticle

@article{30d2ef8d1ca74565a2eeee447ae99969,
title = "CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells",
abstract = "The Ras/ERK (extracellular signal-regulated protein kinase) and cAMP/PKA (protein kinase A) pathways are essential for the transcriptional activities of CREB (cAMP response element binding protein) and MITF (microphthalmia-associated transcription factor) in melanogenesis and the progression of melanoma. However, the interaction between Ras/ERK and cAMP/PKA pathways in the melanogenesis and progression of melanoma is not fully known. Here, we report that CSE1L (chromosome segregation 1-like protein) regulates cAMP/PKA-induced CREB and MITF expressions as well as Ras-induced ERK1/2 phosphorylation. IBMX, a cAMP/PKA activator, treatment induced CSE1L phosphorylation and augmented Ras-induced ERK1/2 phosphorylation. CSE1L knockdown by CSE1L shRNA expression vectors inhibited Ras-induced ERK1/2 phosphorylation and melanogenesis in melanoma cells. CSE1L overexpression increased phospho-CREB expression; CSE1L knockdown also inhibited Ras-induced phospho-CREB, MITF, and tyrosinase expressions, regardless of the presence of IBMX. This study identifies CSE1L links and controls the Ras/ERK and cAMP/PKA pathways in the melanogenesis of melanoma cells. Melanomas frequently develop drug resistance via paradoxical activation of Ras/Raf/MEK/ERK or alternatively activated Ras/ERK and cAMP/PKA pathways. Thus CSE1L may be a potential target for treating melanomas that harbor Ras mutations or are resistant to drugs targeting Raf/MEK/ERK.",
keywords = "CREB, CSE1L, ERK1/2, Melanoma, MITF, Ras",
author = "Lee, {Woan Ruoh} and Shen, {Shing Chuan} and Wu, {Pei Ru} and Chou, {Chia Lun} and Shih, {Yi Hsien} and Yeh, {Chung Min} and Yeh, {Kun Tu} and Jiang, {Ming Chung}",
year = "2016",
month = "11",
doi = "10.1002/mc.22407",
language = "English",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
publisher = "Wiley-Liss Inc.",

}

TY - JOUR

T1 - CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells

AU - Lee, Woan Ruoh

AU - Shen, Shing Chuan

AU - Wu, Pei Ru

AU - Chou, Chia Lun

AU - Shih, Yi Hsien

AU - Yeh, Chung Min

AU - Yeh, Kun Tu

AU - Jiang, Ming Chung

PY - 2016/11

Y1 - 2016/11

N2 - The Ras/ERK (extracellular signal-regulated protein kinase) and cAMP/PKA (protein kinase A) pathways are essential for the transcriptional activities of CREB (cAMP response element binding protein) and MITF (microphthalmia-associated transcription factor) in melanogenesis and the progression of melanoma. However, the interaction between Ras/ERK and cAMP/PKA pathways in the melanogenesis and progression of melanoma is not fully known. Here, we report that CSE1L (chromosome segregation 1-like protein) regulates cAMP/PKA-induced CREB and MITF expressions as well as Ras-induced ERK1/2 phosphorylation. IBMX, a cAMP/PKA activator, treatment induced CSE1L phosphorylation and augmented Ras-induced ERK1/2 phosphorylation. CSE1L knockdown by CSE1L shRNA expression vectors inhibited Ras-induced ERK1/2 phosphorylation and melanogenesis in melanoma cells. CSE1L overexpression increased phospho-CREB expression; CSE1L knockdown also inhibited Ras-induced phospho-CREB, MITF, and tyrosinase expressions, regardless of the presence of IBMX. This study identifies CSE1L links and controls the Ras/ERK and cAMP/PKA pathways in the melanogenesis of melanoma cells. Melanomas frequently develop drug resistance via paradoxical activation of Ras/Raf/MEK/ERK or alternatively activated Ras/ERK and cAMP/PKA pathways. Thus CSE1L may be a potential target for treating melanomas that harbor Ras mutations or are resistant to drugs targeting Raf/MEK/ERK.

AB - The Ras/ERK (extracellular signal-regulated protein kinase) and cAMP/PKA (protein kinase A) pathways are essential for the transcriptional activities of CREB (cAMP response element binding protein) and MITF (microphthalmia-associated transcription factor) in melanogenesis and the progression of melanoma. However, the interaction between Ras/ERK and cAMP/PKA pathways in the melanogenesis and progression of melanoma is not fully known. Here, we report that CSE1L (chromosome segregation 1-like protein) regulates cAMP/PKA-induced CREB and MITF expressions as well as Ras-induced ERK1/2 phosphorylation. IBMX, a cAMP/PKA activator, treatment induced CSE1L phosphorylation and augmented Ras-induced ERK1/2 phosphorylation. CSE1L knockdown by CSE1L shRNA expression vectors inhibited Ras-induced ERK1/2 phosphorylation and melanogenesis in melanoma cells. CSE1L overexpression increased phospho-CREB expression; CSE1L knockdown also inhibited Ras-induced phospho-CREB, MITF, and tyrosinase expressions, regardless of the presence of IBMX. This study identifies CSE1L links and controls the Ras/ERK and cAMP/PKA pathways in the melanogenesis of melanoma cells. Melanomas frequently develop drug resistance via paradoxical activation of Ras/Raf/MEK/ERK or alternatively activated Ras/ERK and cAMP/PKA pathways. Thus CSE1L may be a potential target for treating melanomas that harbor Ras mutations or are resistant to drugs targeting Raf/MEK/ERK.

KW - CREB

KW - CSE1L

KW - ERK1/2

KW - Melanoma

KW - MITF

KW - Ras

UR - http://www.scopus.com/inward/record.url?scp=84940774931&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940774931&partnerID=8YFLogxK

U2 - 10.1002/mc.22407

DO - 10.1002/mc.22407

M3 - Article

C2 - 26331446

AN - SCOPUS:84940774931

JO - Molecular Carcinogenesis

JF - Molecular Carcinogenesis

SN - 0899-1987

ER -