The negative c-Myc target onzin affects proliferation and apoptosis via its obligate interaction with phospholipid scramblase 1.
Onzin, the product of a negatively c-Myc-regulated target gene, is highly expressed in myeloid cells. As a result of its interaction with and activation of Akt1 and Mdm2, onzin down-regulates p53. The apoptotic sensitivity of several cell lines is thus directly related to onzin levels. We have conducted a search for additional onzin-interacting proteins and identified phospholipid scramblase 1 (PLSCR1), an endofacial membrane protein, which is proposed to mediate the bidirectional movement of plasma membrane phospholipids during proliferation and apoptosis. PLSCR1 interacts with the same cysteine-rich domain of onzin as do Akt1 and Mdm2, whereas the onzin-interacting domain of PLSCR1 centers around, but does not require, a previously identified palmitoylation signal. Depletion of endogenous PLSCR1 in myeloid cells leads to a phenotype that mimics that of onzin overexpression, providing evidence that PLSCR1 is a physiologic regulator of onzin. In contrast, PLSCR1 overexpression in fibroblasts, which normally do not express onzin, affects neither growth nor apoptosis unless onzin is coexpressed, in which case PLSCR1 completely abrogates onzin's positive effects on proliferation and survival. These findings demonstrate a functional interdependence between onzin and PLSCR1. They further suggest a contiguous link between the earliest events mediated by c-Myc and the latest ones, which culminate at the cell surface and lead to phospholipid reshuffling and cell death.
Li
Youjun
Y
Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Room 8124, Rangos Research Center, 3460 Fifth Ave., Pittsburgh, PA 15213, USA.
Rogulski
Kenneth
K
Zhou
Quansheng
Q
Sims
Peter J
PJ
Prochownik
Edward V
EV
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000235:genetics; D051379:Mice; D022423:Myeloid Cells / Q000737:chemistry / Q000378:metabolism; D015513:Oncogene Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D015513:Oncogene Proteins; D049294:Phospholipid Transfer Proteins; C493426:Plscr1 protein, mouse; D016159:Tumor Suppressor Protein p53; C506003:onzin protein, mouse; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt