title: p27kip1 protein levels reflect a nexus of oncogenic signaling during cell transformation.
abstract: SV40 small t-antigen (ST) collaborates with SV40 large T-antigen (LT) and activated rasv12 to promote transformation in a variety of immortalized human cells. A number of oncogenes or the disruption of the general serine-threonine phosphatase protein phosphatase 2A (PP2A) can replace ST in this paradigm. However, the relationship between these oncogenes and PP2A activity is not clear. To address this, we queried the connectivity of these molecules in silico. We found that p27 was connected to each of those oncogenes that could substitute for ST. We further determined that p27 loss can substitute for the expression of ST during transformation of both rodent and human cells. Conversely, knock-in cells expressing the degradation-resistant S10A and T187A mutants of p27 were resistant to the transforming activities of ST. This suggests that p27 is an important target of the tumor-suppressive effects of PP2A and likely an important target of the multitude of cellular oncoproteins that emulate the transforming function of ST.
authors.affiliation: Department of Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Miller
authors.forename: Nancy
authors.initials: N
authors.lastname: Yeh
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Hofstetter
authors.forename: Doruk
authors.initials: D
authors.lastname: Keskin
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Goldstein
authors.forename: Andrew
authors.initials: A
authors.lastname: Koff
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis
chemical_list: D000952:Antigens, Polyomavirus Transforming; C436291:CDKN1B protein, human; C493961:Cdkn1b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054648:Protein Phosphatase 2