title: Pathologic expression of MHC class II is driven by mitogen-activated protein kinases.
abstract: The class II transactivator (CIITA) is the master regulator of MHC class II molecules (MHC II). In melanoma, the MHC II are constitutively expressed due to an abnormal transcription of CIITA from its promoter III (pIII), and requires the presence of a 1-kb enhancer located upstream from this latter. Since mitogen-activated protein kinases (MAPK) have been shown to be activated in most melanomas, we sought to analyze their possible involvement in CIITA expression. Using chemical inhibitors and dominant-negative constructs of MAPK-ERK kinase (Mek1) and MAPK-JNK, we evidenced the inhibition of MHC II and CIITA expression in melanoma cell lines displaying activated MAPK. Transcriptional regulation by MAPK is known to involve the AP-1 transcription factor family. Sequence analysis revealed an AP-1-responsive motif in the enhancer of CIITA pIII at -5954/-5947 from the site of transcription initiation. Its mutagenesis reduced CIITA expression four- to fivefold in melanoma cell lines and alleviated the effect of dominant-negative constructs of the MAPK pathway. Together, our findings demonstrate that MAPK-ERK and MAPK-JNK are regulators of CIITA transcription in melanoma, and pinpoint an AP-1-responsive site in the CIITA gene pIII. This should have considerable impact on our understanding of the physio-pathologic expression of MHC II.
authors.affiliation: INSERM U662, Institut Universitaire d'Hematologie, University Paris 7, Hopital St Louis, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Martins
authors.forename: Frederique
authors.initials: F
authors.lastname: Deshayes
authors.forename: Fabrice
authors.initials: F
authors.lastname: Baton
authors.forename: Antoine
authors.initials: A
authors.lastname: Forget
authors.forename: Iwona
authors.initials: I
authors.lastname: Ciechomska
authors.forename: Khaoussou
authors.initials: K
authors.lastname: Sylla
authors.forename: Fawzi
authors.initials: F
authors.lastname: Aoudjit
authors.forename: Dominique
authors.initials: D
authors.lastname: Charron
authors.forename: Reem
authors.initials: R
authors.lastname: Al-Daccak
authors.forename: Catherine
authors.initials: C
authors.lastname: Alcaide-Loridan
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; D020928:Mitogen-Activated Protein Kinases