Inhibition of cell cycle progression by a synthetic peptide corresponding to residues 65-79 of an HLA class II sequence: functional similarities but mechanistic differences with the immunosuppressive drug rapamycin.
A synthetic peptide corresponding to a region of the alpha1 alpha-helix of DQA03011 (DQ 65-79) inhibits the proliferation of human PBL and T cells in an allele-nonspecific manner. It blocks proliferation stimulated by anti-CD3 mAb, PHA-P, and alloantigen, but not by PMA and ionomycin. Substitution of each amino acid with serine shows that residues 66, 68, 69, 71-73, and 75-79 are critical for function. Inhibition of proliferation is long lasting and is not reversible with exogenous IL-2. The peptide can be added 24 to 48 h after stimulation and still block proliferation. The DQ 65-79 peptide does not affect expression of IL-2 or IL-2R; however, IL-2-stimulated proliferation is inhibited. Cell cycle progression is blocked at the G1/S transition, and the activity of cdk2 (cyclin-dependent kinase 2) kinase is impaired by the continued presence of p27. Although these results suggest a mechanism similar to that of rapamycin, the peptide inhibition is not reversed with FK-506, which indicates a distinct mechanism.
Boytim
M L
ML
Department of Cardiothoracic Surgery, Stanford University, CA 94305, USA.
Lyu
S C
SC
Jung
R
R
Krensky
A M
AM
Clayberger
C
C
D000595:Amino Acid Sequence; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006131:Growth Inhibitors / Q000276:immunology* / Q000494:pharmacology; D006683:HLA-DQ Antigens / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology; D011090:Polyenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017386:Sequence Homology, Amino Acid; D020123:Sirolimus; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013997:Time Factors
D006131:Growth Inhibitors; D006683:HLA-DQ Antigens; D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D011090:Polyenes; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D020123:Sirolimus; D016559:Tacrolimus