Using cellular models of Pin1 knockout and Pin1 knockdown, we have demonstrated that lowering Pin1 levels changed the intracellular localization and the processing of A beta PP. Under these conditions, less A beta PP was retained at the plasma membrane favoring the amyloidogenic processing, and the kinetics of A beta PP internalization increased as well as the nuclear trafficking of A beta PP C-terminal fragment AICD. In addition, A beta PPThr668Ala mutant, which cannot bind to Pin1 and retains
more trans conformation, rescued the levels of A beta PP at the plasma membrane in Pin1 knockout cells. CP-456773 price Thus, loss of Pin1 function contributes to amyloidogenic pathways, by facilitating both the removal of A beta PP from compartments where it is mostly non-amyloidogenic and its internalization to more amyloidogenic compartments. These data suggest that physiological levels of Pin1 are important to control the intracellular localization and metabolic fate of Thr668-phosphorylated A beta PP, and regulation of A beta PP conformation is especially important in pathologic conditions of A beta PP hyperphosphorylation and/or loss of Pin1 function, associated with AD.”
“The transient receptor potential cation channel, subfamily M, member 1 (TRPM1/Melastatin-1/MLSN-1) expression has been shown to have prognostic
utility in the evaluation of primary cutaneous melanoma. We analyzed a learn more series of spindled and epithelioid cell nevi (Spitz) and primary cutaneous nodular melanomas to determine whether the expression of TRPM1 mRNA may be useful in distinguishing between Spitz nevi and nodular melanomas and to further examine the patterns of TRPM1 mRNA expression in cutaneous melanocytic proliferations. Formalin-fixed, paraffin-embedded tissues from 95 Spitz nevi and 33 nodular melanomas were analyzed for the expression of TRPM1 mRNA by in situ hybridization Trichostatin A using (35)S-labeled riboprobes. Ubiquitous melanocytic expression of TRPM1 mRNA was observed in 56 of 95 (59%) Spitz nevi and 4 of 33 (12%) nodular melanomas. Diffusely scattered loss of TRPM1 mRNA was identified in 38
of 95 (40%) Spitz nevi and 2 of 33 (6%) nodular melanomas. Regional loss of the TRPM1 mRNA expression by a significant subset of dermal tumor cells or a complete absence of TRPM1 expression by the dermal tumor was identified in 27 of 33 (82%) nodular melanomas, but only 1 of 95 (1%) Spitz nevi. These findings suggest that the pattern of TRPM1 mRNA expression may be helpful in the differentiation of Spitz nevi and nodular melanomas. Of the 16 patients who experienced metastasis, 15 (94%) had primary tumors that displayed reduced MLSN mRNA expression by all or a part of the dermal tumor. Modern Pathology (2009) 22, 969-976; doi: 10.1038/modpathol.2009.56; published online 24 April 2009″
“Background: Papaya (Carica papaya L.) is a commercially important crop that produces climacteric fruits with a soft and sweet pulp that contain a wide range of health promoting phytochemicals.