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. © 2015 Wiley Periodicals, Inc.

JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component

“…Melanin synthesis is a unique characteristic of melanoma and a complex process involving microphthalmia-associated transcription factor (MITF), a transcription factor and a master regulator of melanogenesis, whose expression itself is activated by the MAPK signaling [ 38 – 40 ]. In order to understand the biological significance of the regulation of the MAPK signaling by JMJD6, we next investigated the effect of JMJD6 on melanogenesis.…”

Intermittent parathyroid hormone promotes cementogenesis in a PKA‐ and ERK1/2‐dependent manner

“…Lee et al. demonstrated that cAMP/PKA and Ras/ERK pathways were linked together and regulated the expressions and phosphorylation of ERK1/2 in melanoma cells . Research on dental papilla cells revealed ERK1/2 and PKA signaling were involved in the regulation of fibroblast growth factor‐2 by extracellular calcium .…”

Precise role of dermal fibroblasts on melanocyte pigmentation

“…cAMP/PKA (cyclic adenosine monophosphate/protein kinase A) signaling can also contribute to MITF expression. Activation of some melanocyte receptors with their ligands (eg, melanocortin receptor MCR-1) results in increased levels of intracellular cAMP and activation of PKA [17]. PKA phosphorylates cAMP responsive element binding protein (CREB) which acts as a transcription factor of MITF.…”