PMID- 8594303
OWN - NLM
STAT- MEDLINE
DCOM- 19960408
LR  - 20220309
IS  - 0024-3205 (Print)
IS  - 0024-3205 (Linking)
VI  - 58
IP  - 5
DP  - 1996
TI  - Mechanism of action of the immunosuppressant rapamycin.
PG  - 373-95
AB  - Rapamycin has potent immunosuppressive properties reflecting its ability to 
      disrupt cytokine signaling that promotes lymphocyte growth and differentiation. 
      In IL-2-stimulated T cells, rapamycin impedes progression through the G1/S 
      transition of the proliferation cycle, resulting in a mid-to-late G1 arrest. Two 
      major biochemical alterations underlie this mode of action. The first one affects 
      the phosphorylation/activation of the p70 S6 kinase (p70s6k), an early event of 
      cytokine-induced mitogenic response. By inhibiting this enzyme, whose major 
      substrate is the 40S ribosomal subunit S6 protein, rapamycin reduces the 
      translation of certain mRNA encoding for ribosomal proteins and elongation 
      factors, thereby decreasing protein synthesis. A second, later effect of 
      rapamycin in IL-2-stimulated T cells is an inhibition of the enzymatic activity 
      of the cyclin-dependent kinase cdk2-cyclin E complex, which functions as a 
      crucial regulator of G1/S transition. This inhibition results from a prevention 
      of the decline of the p27 cdk inhibitor, that normally follows IL-2 stimulation. 
      To mediate these biochemical alterations, rapamycin needs to bind to 
      intracellular proteins, termed FKBP, thereby forming a unique effector molecular 
      complex. However, neither(p70s6k) inhibition, nor p27-induced cdk2-cyclin E 
      inhibition are directly caused by the FKBP-rapamycin complex. Instead, this 
      complex physically interacts with a novel protein, designated "mammalian target 
      of rapamycin" (mTOR), which has sequence homology with the catalytic domain of 
      phosphatidylinositol kinases and may therefore be itself a kinase. mTOR may act 
      upstream of (p70s6K) and cdk2-cyclin E in a linear or bifurcated pathway of 
      growth regulation. Molecular dissection of this pathway should further unravel 
      cytokine-mediated signaling processes and help devise new immunosuppressants.
FAU - Dumont, F J
AU  - Dumont FJ
AD  - Department of Immunology, Merck Research Laboratories, Rahway, NJ 07065, USA.
FAU - Su, Q
AU  - Su Q
LA  - eng
PT  - Journal Article
PT  - Review
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Carrier Proteins)
RN  - 0 (Cyclins)
RN  - 0 (Cytokines)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Polyenes)
RN  - 0 (RNA, Messenger)
RN  - 0 (Ribosomal Proteins)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.22 (CDC2-CDC28 Kinases)
RN  - EC 2.7.11.22 (CDK2 protein, human)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 5.2.1.- (Tacrolimus Binding Proteins)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - *CDC2-CDC28 Kinases
MH  - Carrier Proteins/metabolism
MH  - Cell Cycle/drug effects
MH  - Cell Differentiation/drug effects
MH  - Cell Division/drug effects
MH  - Cyclin-Dependent Kinase 2
MH  - Cyclin-Dependent Kinases/metabolism
MH  - Cyclins/metabolism
MH  - Cytokines/physiology
MH  - DNA-Binding Proteins/metabolism
MH  - Heat-Shock Proteins/metabolism
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Lymphocyte Activation
MH  - Phosphorylation
MH  - Polyenes/*pharmacology
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - RNA, Messenger/metabolism
MH  - Ribosomal Protein S6 Kinases
MH  - Ribosomal Proteins/biosynthesis
MH  - Signal Transduction/drug effects
MH  - Sirolimus
MH  - T-Lymphocytes/cytology/*drug effects/immunology
MH  - Tacrolimus Binding Proteins
RF  - 196
EDAT- 1996/01/01 00:00
MHDA- 1996/01/01 00:01
CRDT- 1996/01/01 00:00
PHST- 1996/01/01 00:00 [pubmed]
PHST- 1996/01/01 00:01 [medline]
PHST- 1996/01/01 00:00 [entrez]
AID - 0024320595022333 [pii]
AID - 10.1016/0024-3205(95)02233-3 [doi]
PST - ppublish
SO  - Life Sci. 1996;58(5):373-95. doi: 10.1016/0024-3205(95)02233-3.