title: The signal peptide of mouse mammary tumor virus-env: a phosphoprotein tumor modulator.
abstract: Mouse mammary tumor virus (MMTV) is associated primarily with mammary carcinomas and lymphomas. The signal peptide of the MMTV envelope precursor is uniquely targeted to nucleoli of cells that harbor the virus, where it can function as a nuclear export factor for intron-containing transcripts. Antibodies to this signal peptide, which we refer to as p14, were previously shown to label nucleoli in a subset of human breast cancers. To look for additional cellular functions of p14, different mutants were ectopically expressed in the MCF-7 human breast cancer cell line. This approach identified motifs responsible for its nucleolar targeting, nucleocytoplasmic shuttling, target protein (B23, nucleophosmin) binding, and phosphorylation at serine 18 and 65 both in situ and in vitro. To test the role of these phosphorylation sites, we carried out in vivo tumorigenesis studies in severe combined immunodeficient mice. The findings show that the p14-Ser65Ala mutation is associated with impaired tumorigenicity, whereas the p14-Ser18Ala mutation is associated with enhanced tumorigenicity. Microarray analysis suggests that phosphorylation at serine 18 or at serine 65 is associated with transcriptional regulation of the L5 nucleolar ribosomal protein (a p14 target) and the Erb-B signal transduction pathway. Taken together, these results show that the phosphorylation status of p14 determines whether it functions as a pro-oncogenic or antioncogenic modulator.
authors: Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Dafna
authors: D
authors: Feldman
authors: Maayan
authors: M
authors: Roniger
authors: Allan
authors: A
authors: Bar-Sinai
authors: Ori
authors: O
authors: Braitbard
authors: Carmit
authors: C
authors: Natan
authors: Dona C
authors: DC
authors: Love
authors: John A
authors: JA
authors: Hanover
authors: Jacob
authors: J
authors: Hochman
mesh_terms: D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D021382:Protein Sorting Signals / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D010750:Phosphoproteins; D021382:Protein Sorting Signals; D012269:Ribosomal Proteins; D014759:Viral Envelope Proteins