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Molecular and Cellular Biology, May 2006, p. 3401-3413, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3401-3413.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Negative c-Myc Target Onzin Affects Proliferation and Apoptosis via Its Obligate Interaction with Phospholipid Scramblase I

Section of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania,¹ Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California,² Department of Molecular Genetics and Biochemistry, University of Pittsburgh Medical Center,³ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania⁴

Received 26 August 2005/ Returned for modification 3 October 2005/ Accepted 10 February 2006

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.

This is paper no. 17685-MEM from the Scripps Research Institute.

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