Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a reversible G0-like arrest.
Alpha interferon is a potent growth inhibitor of Daudi Burkitt's lymphoma cells. We show here that alpha-interferon signaling interacted simultaneously with several components of the basic cell cycle machinery, causing cells to enter into a state that had many features characteristic of the G0 state. Within a few hours after alpha-interferon treatment, cyclin D3 mRNA and protein levels dropped to undetectable levels and, in parallel, the activities of cyclin A- and cyclin E-associated kinases were significantly reduced. The latter resulted from the rapid alpha-interferon-mediated elimination of cdc25A, a phosphatase that is required for antagonism of negative tyrosine phosphorylation of cdk2 in cyclin-cdk complexes. This regulation represents a novel mechanism through which an external inhibitory cytokine interacts with the cell cycle machinery. At later time points after alpha-interferon treatment, the levels of the 55-kDa slowly migrating hyperphosphorylated form of cyclin E and of cyclin A were also reduced. The antiproliferative effects were reversible, and cultures from which alpha interferon was removed reentered S phase after a lag that typically corresponded to approximately two doubling times. During this lag period, the expression of cyclin D3 and cyclin A, as well as of the cdc25A phosphatase, continued to be switched off, in spite of the removal of alpha interferon from the cell surface. In contrast, c-myc, which represents another downstream target gene that is subjected to negative regulation by alpha interferon, was relieved from suppression much earlier, concomitant with the decay in early signaling of the cytokine. The delayed pattern of cyclin reexpression provides evidence that alpha-interferon signaling imposes a G0-like state on this system.
Tiefenbrun
N
N
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
Melamed
D
D
Levy
N
N
Resnitzky
D
D
Hoffman
I
I
Reed
S I
SI
Kimchi
A
A
D002051:Burkitt Lymphoma; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D056743:Cyclin D3; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis* / Q000302:isolation & purification; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007700:Kinetics; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis* / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D013489:Suppression, Genetic; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases
C534696:CCND3 protein, human; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D016213:Cyclins; D016898:Interferon-alpha; D018844:Cyclin-Dependent Kinases; D010749:Phosphoprotein Phosphatases; D020687:cdc25 Phosphatases; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate