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Proliferating Cell Nuclear Antigen as the Cell Cycle Sensor for an HLA-Derived Peptide Blocking T Cell Proliferation¹

Xuefeng Ling^*, Salar Kamangar^*, Michelle L. Boytim, Zvi Kelman^§, Philip Huie, Shu-Chen Lyu, Richard K. Sibley, Jerard Hurwitz^§, Carol Clayberger^*, and Alan M. Krensky^2,*

Departments of ^* Pediatrics, Cardiothoracic Surgery, and Pathology, Stanford University, Stanford, CA 94305; and ^§ Department of Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Synthetic peptides corresponding to structural regions of HLA molecules are novel immunosuppressive agents. A peptide corresponding to residues 65–79 of the -chain of HLA-DQA03011 (DQ65–79) blocks cell cycle progression from early G₁ to the G₁ restriction point, which inhibits cyclin-dependent kinase-2 activity and phosphorylation of the retinoblastoma protein. A yeast two-hybrid screen identified proliferating cell nuclear Ag (PCNA) as a cellular ligand for this peptide, whose interaction with PCNA was further confirmed by in vitro biochemistry. Electron microscopy demonstrates that the DQ65–79 peptide enters the cell and colocalizes with PCNA in the T cell nucleus in vivo. Binding of the DQ65–79 peptide to PCNA did not block polymerase (pol )-dependent DNA replication in vitro. These findings support a key role for PCNA as a sensor of cell cycle progression and reveal an unanticipated function for conserved regions of HLA molecules.

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