Constitutive and IFNγ-induced activation of MHC2TA promoter type III in human melanoma cell lines is governed by separate regulatory elements within the PIII upstream regulatory region

Cell lines established from tumor tissue of cutaneous melanoma biopsies often display constitutive and IFN gamma-inducible expression of MHC class 11 molecules. The expression of MHC class 11 molecules in melanoma is associated with an overall poor prognosis and unfavorable clinical outcome. We have analyzed the DNA elements and interacting transcription factors that control the constitutive and IFN gamma-inducible expression of the class 11 transactivator (CIITA), a co-activator essential for transcription of all MHC class 11 genes. Our studies reveal the activation of multiple CIITA promoter regions (CIITA-PII, -PIII and -PIV) in melanoma cell lines for both the constitutive and IFN-gamma-inducible expression of MHC class 11 molecules. Furthermore, we show that constitutive and IFN-gamma-inducible expression of the CIITA-PIII isoform is governed by separate regulatory elements within the PIII upstream regulatory region (PURR). Similarly constitutive activation in melanoma of CIITA-PII, CIITA-PIII, and CIITA-PIV does not require components of the IFN gamma signaling pathway. However, these components are readily recruited to the PURR and CIITA-PIV after exposure of cells to IFN gamma and account for the IFN gamma-induced expression of CIITA. Together, our data reveal the contribution of distinct elements and factors in the constitutive and IFN gamma-inducible expression of CIITA in melanoma cell lines of the skin. (c) 2006 Elsevier Ltd. All rights reserved.