RESUMO
RASSF family proteins are tumor suppressors that are frequently downregulated during the development of human cancer. The best-characterized member of the family is RASSF1A, which is downregulated by promoter methylation in 40-90% of primary human tumors. We now identify and characterize a novel member of the RASSF family, RASSF6. Like the other family members, RASSF6 possesses a Ras Association domain and binds activated Ras. Exogenous expression of RASSF6 promoted apoptosis, synergized with activated K-Ras to induce cell death and inhibited the survival of specific tumor cell lines. Suppression of RASSF6 enhanced the tumorigenic phenotype of a human lung tumor cell line. Furthermore, RASSF6 is often downregulated in primary human tumors. RASSF6 shares some similar overall properties as other RASSF proteins. However, there are significant differences in biological activity between RASSF6 and other family members including a discrete tissue expression profile, cell killing specificity and impact on signaling pathways. Moreover, RASSF6 may play a role in dictating the degree of inflammatory response to the respiratory syncytial virus. Thus, RASSF6 is a novel RASSF family member that demonstrates the properties of a Ras effector and tumor suppressor but exhibits biological properties that are unique and distinct from those of other family members.
Assuntos
Proteínas Monoméricas de Ligação ao GTP/fisiologia , Família Multigênica , Proteínas Supressoras de Tumor/fisiologia , Sequência de Aminoácidos , Animais , Proteínas Reguladoras de Apoptose , Linhagem Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Inibidores do Crescimento/biossíntese , Inibidores do Crescimento/química , Inibidores do Crescimento/fisiologia , Humanos , Camundongos , Dados de Sequência Molecular , Proteínas Monoméricas de Ligação ao GTP/biossíntese , Proteínas Monoméricas de Ligação ao GTP/química , Proteínas Monoméricas de Ligação ao GTP/genética , Especificidade de Órgãos/genética , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética , Proteínas ras/metabolismoRESUMO
Junctional adhesion molecule 1 (JAM-1) was the first of a family of related proteins (JAM family) to be discovered. Two proteins with structural and sequence similarities to JAM-1, named JAM-2 and JAM-3, have been identified more recently. JAM-1 is specifically localized at the tight junctions of epithelial and endothelial cells and is involved in the regulation of junctional integrity and permeability. This function is attributed to its ability to interact in a homophilic manner. JAM-1 can also bind in a heterophilic manner as it serves as a ligand for integrin LFA-1 (CD11a/CD18), and plays a key role in the process of leukocyte transmigration. In addition, JAM-1 is also a receptor for reovirus, and is a platelet receptor involved in platelet adhesion and antibody-induced platelet aggregation. Further study of the mechanism of JAM-1 action within these diverse systems may demonstrate that JAM-1 is a key player in many different cellular functions.
Assuntos
Moléculas de Adesão Celular/fisiologia , Receptores de Superfície Celular/fisiologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Plaquetas/metabolismo , Moléculas de Adesão Celular/química , Movimento Celular , Mapeamento Cromossômico , Humanos , Leucócitos/metabolismo , Camundongos , Dados de Sequência Molecular , Conformação Proteica , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Ratos , Receptores de Superfície Celular/química , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Junções Íntimas , Distribuição TecidualRESUMO
We have previously reported the purification and characterization of a 32 kDa platelet surface glycoprotein that is recognized by the stimulatory monoclonal antibody, F11. The cDNA has been cloned and found to encode the human homolog of the murine junctional adhesion molecule, JAM; we therefore named this human homolog JAM-1. Northern blot analysis indicated that JAM-1 mRNA is expressed as multiple species, the predominant transcript being approximately 4.0 kb in size. Genetic mapping analysis using fluorescence in situ hybridization (FISH) showed that it is localized to chromosome 1q21.1-21.3. Recombinant JAM-1, when expressed in Chinese hamster ovary (CHO) cells, localized to the cell membrane with intense staining where two adjacent cells actually made contact with each other, suggesting that, similar to murine JAM, human JAM-1 may also localize at the cell-cell junction. In well-spread cells, JAM-1 co-localized with F-actin at the cell-cell contacts and at the membrane ruffles, but not at the stress fibers. Interestingly, JAM-1 localizes only to the cell-cell junctions formed by two transfected cells and not to the cell-cell junctions formed by a transfected cell with an untransfected cell, suggesting that JAM-1 may facilitate cell adhesion through homophilic binding. In addition, human platelets specifically bind to a monolayer of CHO cells expressing human JAM-1, further supporting homophilic interactions. The results presented here indicate that JAM-1, a receptor for a platelet-activating antibody, is the human homolog of the junctional adhesion molecule. JAM-1 is a single copy gene, which is constitutively expressed on various tissues and cells, and may be involved in cell to cell adhesion through homophilic interaction.