title: Molecular basis for the autonomous promotion of cell proliferation by angiogenin.
abstract: Canonical growth factors act indirectly via receptor-mediated signal transduction pathways. Here, we report on an autonomous pathway in which a growth factor is internalized, has its localization regulated by phosphorylation, and ultimately uses intrinsic catalytic activity to effect epigenetic change. Angiogenin (ANG), a secreted vertebrate ribonuclease, is known to promote cell proliferation, leading to neovascularization as well as neuroprotection in mammals. Upon entering cells, ANG encounters the cytosolic ribonuclease inhibitor protein, which binds with femtomolar affinity. We find that protein kinase C and cyclin-dependent kinase phosphorylate ANG, enabling ANG to evade its inhibitor and enter the nucleus. After migrating to the nucleolus, ANG cleaves promoter-associated RNA, which prevents the recruitment of the nucleolar remodeling complex to the ribosomal DNA promoter. The ensuing derepression of rDNA transcription promotes cell proliferation. The biochemical basis for this unprecedented mechanism of signal transduction suggests new modalities for the treatment of cancers and neurological disorders.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Trish T
authors.initials: TT
authors.lastname: Hoang
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA rtraines@wisc.edu.|Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Raines
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D010766:Phosphorylation; D011487:Protein Conformation; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D059367:RNA Cleavage; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D011493:Protein Kinase C; D012335:RNA, Ribosomal; D012259:Ribonuclease, Pancreatic; C436708:BAZ2A protein, human; D000092468:Bromodomain Containing Proteins; C046366:angiogenin