A family of proteins has recently been reported to function in a negative feedback loop to regulate signaling by cytokine receptors via the JAK 1 (Janus kinase)/STAT(signal transducer and activator of transcription) pathway (1-9). The first member of this family to be reported was mouse CIS (cytokine inducible SH2-containing protein) (1). Upon binding of ligand to cytokine receptors, receptor-associated JAKs become activated and phosphorylate tyrosine residues on the membrane distal portion of the receptor (10). Signaling molecules which subsequently bind to these phosphotyrosine containing motifs on the receptor include members of the STAT family. STATs are phosphorylated by cytokine receptor-associated JAKs, form dimers, and travel to the nucleus where they activate transcription. CIS was isolated as a cytokine responsive immediateearly gene in mouse hematopoietic cells (1, 2). CIS mRNA encodes a polypeptide of 257 amino acids that contains an SH2 domain in the middle of the molecule. Expression of CIS in IL-3-dependent hematopoietic cell lines reduced the growth rate of the transformants, suggesting a negative role of CIS in signal transduction. The CIS protein associated with tyrosinephosphorylated erythropoietin (EPO) receptor and the tyrosine-phosphorylated  chain of the IL-3 receptor, presumably by binding of the CIS SH2 domain to phosphotyrosine containing motifs in the receptors. A mutant IL-2 receptor that failed to activate STAT5 could not induce CIS, suggesting that STAT5 was important for cytokine induction of CIS. Indeed, upstream of the transcription initiation site in the CIS promoter are four potential STAT5-binding sites. Expression of STAT5 and the EPO receptor in HEK293 cells conferred EPOdependent activation of the CIS promoter. In these cells, EPOdependent tyrosine phosphorylation of STAT5 was suppressed when CIS was coexpressed. Taken together, these results provide evidence for a negative feedback loop in which CIS is induced by the cytokine and then binds to the cytokine receptor, preventing the activation of STAT by JAKs (1, 2). Subsequently, three CIS-related proteins were described and these proteins have been designated as SSI (STAT-induced STAT inhibitor) or SOCS (suppressor of cytokine signaling) proteins 1-3 (3-7, 9). Together with CIS, SSI/SOCS proteins share a common domain structure consisting of an NH 2 -terminal region of variable length, a central SH2 domain and a COOHterminal motif, termed the SOCS box, of unknown function. In contrast to cytokine receptors which do not have intrinsic tyrosine kinase activity but utilize JAKs for receptor phosphorylation and phosphorylation of downstream signaling molecules such as STATs, the insulin-like growth factor I (IGF-I) receptor is a member of the tyrosine kinase family of growth factor receptors (11,12). The IGF-I receptor is important for cellular growth, differentiation, and inhibition of apoptosis. Binding of IGF-I or IGF-II to the IGF-I receptor results in receptor autophosphorylation. Receptor autophosphorylation amplifies t...
Simian virus 40 (SV40) mutants d11066 and d11140 contain deletions within the region encoding the carboxyl terminus of the large tumor (T) antigen. Although these mutations have little effect on the efficiency of viral DNA replication, they decrease the yield of infectious virus particles by 3-4 orders of magnitude [Pipas, J. (1985) J. Virol. 54,[569][570][571][572][573][574][575]. Here we show that the level of late RNA is lower by a factor of 5-15 in CV-1P monkey cells infected with these mutants compared to cells infected with wild-type SV40. Consistent with this decrease in RNA, synthesis of late viral structural proteins VP1 and VP3 decreases by a factor of 5-15. In contrast, the synthesis of SV40 agnoprotein decreases by a factor >100. Intercistronic complementation of these mutants with pm1493 and d1121, two SV40 mutants that are defective in agnoprotein but encode wild-type T antigen, results in an increased synthesis of agnoprotein in the infected cells. These results suggest that the carboxyl-terminal portion of T antigen participates in the posttranscriptional regulation of agnoprotein.Simian virus 40 (SV40) is a small DNA tumor virus that has served as a model system for studies of eukaryotic gene regulation (1). The virus produces a lytic infection of African green monkey kidney cells in which its genes are expressed temporally in two phases. Prior to the onset of DNA replication, an early set of genes encoding large (T) and small (t) tumor antigens is expressed. After the onset of DNA replication the major transcriptional program shifts to the expression of the late genes, which encode the agnoprotein and the viral structural proteins VP1, VP2, and VP3 (1-3). While the function of the 61 amino acid agnoprotein is not entirely clear, it appears to play a role in encapsidation, in assembly of the mature viral particles, or in release of virus particles from infected cells (4-6). In addition, the late agnoprotein may play a role in regulation of late gene expression (7-9).The role of T antigen in activating the late phase of the lytic cycle relates in part to its autoregulation of early gene transcription and the initiation of rounds of DNA replication that increases the SV40 template number. Recent studies have suggested that in the absence of DNA replication, T antigen also plays a significant role, both direct and indirect, in activating late transcription (10-13).Mutations in the carboxyl terminus of T antigen (14,15) have an interesting phenotype in that, although a minimal decrease in the efficiency of viral DNA replication is observed, under appropriate conditions they decrease the yield of infectious virus particles by 3 orders of magnitude (14).This reduction of plaque formation occurs on BSC-40 cells at 32°C or on CV-1P cells at 32°C or 37°C. The present study was conducted to determine the effect of these T-antigen mutants on the levels of late viral RNA or capsid protein. MATERIALS AND METHODSCells and Viruses. The cells used in these experiments were established CV-1P and BSC-40 A...
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