CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells.
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. © 2015 Wiley Periodicals, Inc.
Department of Dermatology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.|Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Woan-Ruoh
WR
Lee
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Shing-Chuan
SC
Shen
Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.|Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
Pei-Ru
PR
Wu
Department of Dermatology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.|Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Chia-Lun
CL
Chou
Department of Dermatology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.|Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Yi-Hsien
YH
Shih
Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.|Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
Chung-Min
CM
Yeh
Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.|School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Kun-Tu
KT
Yeh
Department of Dermatology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan. jiangmwd@gmail.com.
Ming-Chung
MC
Jiang
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D029563:Cellular Apoptosis Susceptibility Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D018631:ras Proteins / Q000378:metabolism
D029563:Cellular Apoptosis Susceptibility Protein; D018631:ras Proteins; D015056:1-Methyl-3-isobutylxanthine
CREB; CSE1L; ERK1/2; MITF; Ras; melanoma