International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 146 - "DISRUPTION OF THE TGF-b PATHWAY, BY A NOVEL LIGAND DEPENDANT MECHANISM IN A MURINE PLASMACYTOMA MODEL "

T Fernandez
National Cancer Institute

2)Tony Parks, 1) Wolfraim L, 1) Potter M, 1)Letterio J
1) National Cancer Research Institute, 2) University of Washington, Seattle

Murine plasmacytomas are tumors of immunoglobulin-secreting plasma cells that can be induced in genetically susceptible BALB/c mice by the intraperitoneal injection of poorly metabolisable alkanes. TGF-b being a potent negative regulator of the proliferation and differentiation of B lymphocytes, we examined its role in plasmacytomagenesis. We earlier demonstrated that PCTs lack functional TGF-b receptors (TbR) and are resistant to the growth inhibitory effects of TGF-b, this having demonstrated for the first time that interruption of a tumor suppressor pathway contributes to plasmacytomagenesis. Subsequently we went on to prove the presence of both active TGF-b as well as a fully functional TbR  within the cell. We then provided proof of principle that an impediment in receptor trafficking to the cell surface occurs due to intracellular sequestration  of the receptor by  the active TGF-b ligand. Focus on the biosynthesis and trafficking of TbRII indicated that TbRII  within the plasmacytoma does not traffick normally through the endoplasmic reticulum and the Golgi. This again is the first known demonstration of a unique pathway of loss of receptor function through inappropriate ligand-receptor interactions thus defining a novel mechanism for modulating the TGF-b pathway. Studies focused on activation of the ligand and endocytic fate of ligand-receptor complexes are under investigation. We are currently extrapolating our studies to other models of plasmacytomagenesis to ascertain the uniqueness or the universality of this phenomenon.


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