Transcriptional regulation of the 11p15 mucin genes. Towards new biological tools in human therapy, in inflammatory diseases and cancer?

Mucin production and secretion by specialized epithelial cells is a common mechanism used by mammals to protect the underlying mucosae against various injuries (pollutants, pathogens, pH). The expression of mucin genes is cel l- and tissue-specific but is submitted to variations during cell different iation, inflammatory process, and is altered during carcinogenesis. The mol ecular mechanisms responsible for the control of mucin transcription and ex pression are beginning to be understood as mucin gene promoters and regulat ory regions are characterized. The four gel-forming mucin genes, MUC2-MUC5A C-MUC5B-MUC6, are clustered on the p15 arm of chromosome 11. Common regulat ory mechanisms (PKA, PKC, PKG and Ca2+ signaling, Sp1/Sp3) may account for the capability of mucous-secreting cells to express several mucin genes sim ultaneously. In response to an insult or during carcinogenesis, the normal pattern of expression is altered and results from specific answers of the c ell by activating different intracellular signaling pathways. 11p15 mucin g enes are regulated at the transcriptional level by proinflammatory cytokine s (IL-1beta, IL-6, TNF-alpha), pleiotropic cytokines (IL-4, IL-13, IL-9), b acterial exoproduct (LPS), growth factors (EGF, TGF-alpha), lipid mediator (PAF), retinoids and hormones. To date, the only downstream cascade known t o activate mucin gene transcription is the Src/Ras/MAPK/pp90(rsk) cascade, which leads to the activation of the transcription factor NF-kappaB. Mucin gene transcription is also regulated by ATF-1, CREB and RAR-alpha transcrip tion factors. Finally, repression of mucin transcription in cancer cells is under the control of the epigenetic mechanism of methylation. As transcrip tional regulation of mucin genes begins to be unraveled, it becomes clear t hat many signaling pathways are involved. Our understanding of mucin gene t ranscriptional regulation, which awaits more data (identification of the si gnaling cascades and active cis-elements within promoters and introns), wil l most certainly lead to the use of mucin genes as molecular markers in can cer and molecular tools in human gene therapy, and to the synthesis of new therapeutic agents in inflammatory diseases of the epithelium.