Format

Send to

Choose Destination
PLoS One. 2010 Aug 27;5(8):e12452. doi: 10.1371/journal.pone.0012452.

CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma.

Author information

1
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.

Abstract

BACKGROUND:

The loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown.

METHODOLOGY/PRINCIPAL FINDINGS:

Herein, we demonstrate that both inhibition of PKA-dependent CREB phosphorylation, as well as silencing of CREB expression by shRNA, restored AP-2alpha protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha. Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2alpha expression following CREB silencing increases endogenous p21(Waf1) and decreases MCAM/MUC18, both known to be downstream target genes of AP-2alpha involved in melanoma progression.

CONCLUSIONS/SIGNIFICANCE:

Since AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c-KIT, VEGF, PAR-1, MCAM/MUC18, and p21(Waf1), our data identified CREB as a major regulator of the malignant melanoma phenotype.

PMID:
20805990
PMCID:
PMC2929203
DOI:
10.1371/journal.pone.0012452
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center