Human PARM-1 is a novel mucin-like, androgen-regulated gene exhibiting proliferative effects in prostate cancer cells.

In this paper we characterize hPARM-1, the human ortholog of rat PARM-1 (prostatic androgen-repressed message-1) and demonstrate its role in prostate cancer. Immunofluorescence microscopy and ultrastructural analysis revealed the localization of hPARM-1 to Golgi, plasma membrane and the early endocytic pathway but not in lysosomes. Biochemical and deglycosylation studies showed hPARM-1 as a highly glycosylated, mucin-like type I transmembrane protein. Analysis of expression of hPARM-1 in various human tissues revealed its presence in most human tissues with especially high expression in heart, kidney and placenta. Androgen controls the expression of the gene as a marked 7-fold increase is seen in the androgen-dependent prostate cancer cell line, LNCaP on androgen stimulation. This is further supported by its decrease in expression in CWR22 xenograft upon castration. Moreover, ectopic expression of hPARM-1 in PC3 prostate cancer cells increased colony formation, suggesting a probable role in cell proliferation. These results suggest that hPARM-1 may have a role in normal biology of the prostate cell and in prostate cancer.

Re-routing of the invariant chain to the direct sorting pathway by introduction of an AP3-binding motif from LIMP II.

AP3 is a heteromeric adaptor protein complex involved in the biogenesis of late endosomal/lysosomal structures. It recognizes tyrosine- and leucine-based sorting signals present in the cytoplasmic tails or loops of a number of proteins and is thought to be responsible for the direct transport of these proteins from the Golgi network to late endosomal/lysosomal structures. We have previously reported (Rodionov, Höning, Silye, Kongsvik, von Figura, Bakke, 2002. Structural requirements for interactions between leucine-sorting signals and clathrin-associated adaptor protein complex AP3. J. Biol. Chem. 277, 47436-47443) that in vitro binding of AP3 to the leucine signals is dependent on the nature of three residues immediately upstream of the leucine signal and suggested that these three amino acids define whether the protein is sorted to endosomes via the plasma membrane (PM) or traffics directly to the late endosomes/lysosomes. In this paper, we show in vivo evidence that residues favoring AP3 binding introduced into a protein that is transported via the PM such as the invariant chain can re-route such protein into direct sorting to late endosomal/lysosomal structures.