Abstract
Cellular proliferation determines the events leading to the initiation and development of inflammation, immune activation, cancer, atherogenesis, and other disorders associated with aberrant cell proliferation. Cyclin inhibitor p21 plays a unique role in limiting cell cycle progression. However, its effectiveness can only be demonstrated with direct in vitro and in vivo delivery to control aberrant proliferation. We demonstrate that using a protein-transducing domain p21 protein a) localizes within the nuclear compartments of cells, b) interacts with transcription factors, NF-kappaB, and NFATs (NFATc and NFATp), and c) inhibits lymphocyte proliferation and expression of proinflammatory cytokines. This study using lymphocyte proliferation as a model suggests that the recombinant p21 protein can directly be delivered as a therapeutic protein to provide a novel, viable, and powerful strategy to limit proliferation, inflammation, alloimmune activation, cancer, and vascular proliferative disorders such as atherosclerosis.
MeSH terms
-
Active Transport, Cell Nucleus / immunology
-
Cell Cycle Proteins / biosynthesis
-
Cell Cycle Proteins / chemistry
-
Cell Cycle Proteins / isolation & purification
-
Cell Cycle Proteins / physiology*
-
Cell Nucleus / metabolism
-
Cell Proliferation* / drug effects
-
Cyclin-Dependent Kinase Inhibitor p21
-
Cyclosporine / pharmacology
-
Cytokines / antagonists & inhibitors
-
Cytokines / biosynthesis
-
Cytokines / metabolism
-
DNA-Binding Proteins / antagonists & inhibitors
-
DNA-Binding Proteins / metabolism
-
Growth Inhibitors / physiology*
-
Humans
-
Immunosuppressive Agents* / pharmacology
-
Interleukin-2 / antagonists & inhibitors
-
Interleukin-2 / biosynthesis
-
Interleukin-2 / genetics
-
Lymphocyte Activation / drug effects
-
Lymphocyte Subsets / cytology*
-
Lymphocyte Subsets / metabolism*
-
NF-kappa B / antagonists & inhibitors
-
NF-kappa B / metabolism
-
NFATC Transcription Factors
-
Nuclear Proteins / antagonists & inhibitors
-
Nuclear Proteins / metabolism
-
RNA, Messenger / antagonists & inhibitors
-
RNA, Messenger / biosynthesis
-
Recombinant Proteins / metabolism
-
Recombinant Proteins / pharmacology
-
Sirolimus / pharmacology
-
T-Lymphocytes / metabolism
-
Tacrolimus / pharmacology
-
Transcription Factors / antagonists & inhibitors*
-
Transcription Factors / metabolism
Substances
-
CDKN1A protein, human
-
Cell Cycle Proteins
-
Cyclin-Dependent Kinase Inhibitor p21
-
Cytokines
-
DNA-Binding Proteins
-
Growth Inhibitors
-
Immunosuppressive Agents
-
Interleukin-2
-
NF-kappa B
-
NFATC Transcription Factors
-
Nuclear Proteins
-
RNA, Messenger
-
Recombinant Proteins
-
Transcription Factors
-
Cyclosporine
-
Sirolimus
-
Tacrolimus