A Particle-Associated Glycoprotein Signal Peptide Essential for Virus Maturation and Infectivity

Signal peptides (SP) are key determinants for targeting glycoproteins to the secretory pathway. Here we describe the involvement in particle maturation as an additional function of a viral glycoprotein SP. The SP of foamy virus (FV) envelope glycoprotein is predicted to be unusually long. Using an SP-specific antiserum, we demonstrate that its proteolytic removal occurs posttranslationally by a cellular protease and that the major N-terminal cleavage product, gp18, is found in purified viral particles. Analysis of mutants in proposed signal peptidase cleavage positions and N-glycosylation sites revealed an SP about 148 amino acids (aa) in length. FV particle release from infected cells requires the presence of cognate envelope protein and cleavage of its SP sequence. An N-terminal 15-aa SP domain with two conserved tryptophan residues was found to be essential for the egress of FV particles. While the SP N terminus was found to mediate the specificity of FV Env to interact with FV capsids, it was dispensable for Env targeting to the secretory pathway and FV envelope-mediated infectivity of murine leukemia virus pseudotypes

Deletion of RB exons 24 and 25 causes low-penetrance retinoblastoma.

A deletion in the tumor-suppressor gene, RB, discovered by quantitative multiplex PCR, shows low penetrance (LP), since only 39% of eyes at risk in this family develop retinoblastoma. The 4-kb deletion spanning exons 24 and 25 (delta24-25) is the largest ever observed in an LP retinoblastoma family. Unlike the usual RB mutations, which cause retinoblastoma in 95% of at-risk eyes and yield no detectable protein, the delta24-25 allele transcribed a message splicing exon 23 to exon 26, resulting in a detectable protein (pRBdelta24-25) that lacks 58 amino acids from the C-terminal domain, proving that this domain is essential for suppression of retinoblastoma. Two functions were partially impaired by delta24-25-nuclear localization and repression of E2F-consistent with the idea that LP mutations generate "weak alleles" by reducing but not eliminating essential activities. However, delta24-25 ablated interaction of pRB with MDM2. Since a homozygous LP allele is considered nontumorigenic, the pRB/MDM2 interaction may be semi- or nonessential for suppressing retinoblastoma. Alternatively, some homozygous LP alleles may not cause tumorigenesis because an additional event is required (the "three-hit hypothesis"), or the resulting imbalance in pRB function may cause apoptosis (the "death allele hypothesis"). pRBdelta24-25 was also completely defective in suppressing growth of Saos-2 osteosarcoma cells. Targeting pRBdelta24-25 to the nucleus did not improve Saos-2 growth suppression, suggesting that C-terminal domain functions other than nuclear localization are essential for blocking proliferation in these cells. Since delta24-25 behaves like a null allele in these cells but like an LP allele in the retina, pRB may use different mechanisms to control growth in different cell types

Estrogen Regulates the Tumour Suppressor MiRNA-30c and Its Target Gene, MTA-1, in Endometrial Cancer

MicroRNA-30c (miR-30c) has been reported to be a tumour suppressor in endometrial cancer (EC). We demonstrate that miR-30c is down-regulated in EC tissue and is highly expressed in estrogen receptor (ER)-negative HEC-1-B cells. MiR-30c directly inhibits MTA-1 expression and functions as a tumour suppressor via the miR-30c-MTA-1 signalling pathway. Furthermore, miR-30c is decreased upon E(2) treatment in both ER-positive Ishikawa and ER-negative HEC-1-B cells. Taken together, our results suggest that miR-30c is an important deregulated miRNA in EC and might serve as a potential biomarker and novel therapeutic target for EC