Disease relevance of RPH3AL

• Cloning of a human ortholog (RPH3AL) of (RNO)Rph3al from a candidate 17p13.3 medulloblastoma tumor suppressor locus [1].
• Thus, despite its location in a homozygously deleted 17p13.3 locus, it is unlikely that RPH3AL is a gene involved in the oncogenesis of medulloblastoma, FTC, or ovarian cancer [1].
• Somatic RPH3AL mutations were identified, providing support for an authentic role as tumor-suppressor gene in colorectal cancer, but only in a minority of cases [2].
• Furthermore, overexpression of Noc2 inhibited the cell-surface transport of basolateral vesicular stomatitis virus glycoprotein [3].

High impact information on RPH3AL

• A direct inhibitory role for the Rab3-specific effector, Noc2, in Ca2+-regulated exocytosis in neuroendocrine cells [4].
• One putative Rab3A effector in dense-core granule exocytosis is the cytosolic zinc finger protein, Noc2 [4].
• We have established that overexpression of Noc2 in PC12 cells has a direct inhibitory effect upon Ca(2+)-triggered exocytosis in permeabilized cells [4].
• Screening a mouse embryonic cDNA library with the yeast two-hybrid system shows that Noc2 interacts with the LIM domain-containing protein zyxin, a component of the cytoskeleton, and this interaction is further confirmed by the coimmunoprecipitation experiment [5].
• Immunoblot analysis of subcellular fractions of the insulin-secreting cell line MIN6 and immunocytochemistry reveal that Noc2 is a 38-kDa protein present in the cytoplasm [5].

Biological context of RPH3AL

• We determined the exon-intron boundaries of RPH3AL and screened the coding region for mutations by direct sequencing in DNA extracted from 33 tumor samples with allelic loss of 17p13, including 10 medulloblastoma, 14 follicular thyroid cancer (FTC), and 9 ovarian cancer specimens [1].
• Six missense mutations producing amino acid substitution in coding region of the RPH3AL gene were detected in 50 primary colorectal cancer patients [2].
• Silencing of the Noc2 gene by RNA interference led to a strong impairment in the capacity of INS-1E cells to respond to insulin secretagogues, indicating that appropriate levels of Noc2 are essential for pancreatic beta-cell exocytosis [6].

Anatomical context of RPH3AL

• Accordingly, Noc2 is probably involved in regulated exocytosis in endocrine cells by interacting with the cytoskeleton [5].
• Overexpression of Noc2 in PC12 cells cotransfected with growth hormone enhances high K+-induced growth hormone secretion [5].
• Noc2 is expressed predominantly in endocrine tissues and hormone-secreting cell lines and at very low levels in brain [5].
• These data suggest that Noc2 is involved in the recruitment of secretory granules at the plasma membrane possibly via the interaction with Munc13 [6].
• Identification and characterization of Noc2 as a potential Rab3B effector protein in epithelial cells [3].

Associations of RPH3AL with chemical compounds

• We have cloned a cDNA encoding a novel protein of 302 amino acids (designated Noc2, no C2 domain) that has 40.7% amino acid identity with and 77.9% similarity to the N-terminal region of rabphilin-3A, a target molecule of Rab3A [5].
• In this study, we investigated whether Noc2, a Rab27 effector, is involved in isoproterenol (IPR)-stimulated amylase release from acinar cells [7].

Other interactions of RPH3AL

• Mutational analyses of the RPH3AL gene were performed on DNA samples from 50 primary colorectal cancer specimens using polymerase chain reaction-single strand conformation polymorphism, and DNA sequencing [2].
• Protein-protein binding studies revealed that Noc2 is a potential partner of Munc13, a component of the machinery that controls vesicle priming and insulin exocytosis [6].
• In the beta-cell line INS-1E wild-type Noc2, Noc265E, and Noc258A, a mutant capable of interacting with Rab27 but not Rab3, colocalized with insulin-containing vesicles [6].

Analytical, diagnostic and therapeutic context of RPH3AL

• Northern blot analysis revealed that Noc2 mRNA was expressed not only in secretory tissues but also in epithelial tissues and cell lines [3].

References