To understand the molecular bases for cytokine redundancy and pleiotropy, we have compared the Stat proteins activated in peripheral blood lymphocytes (PBLs) by cytokines with shared and distinct actions. Interleukin-2 (IL-2) rapidly activated Stat5 in fresh PBL, and Stat3 and Stat5 in preactivated PBL. IL-7 and IL-15 induced the same complexes as IL-2, a feature explained by the existence of similar tyrosine-phosphorylated motifs in the cytoplasmic domains of IL-2R beta and IL-7R that can serve as docking sites for Stat proteins. IL-13 Induced the same complexes as IL-4, a finding explained by our studies implicating IL-4R as a shared component of the receptors. These studies demonstrate that a single cytokine can activate different combinations of Stat proteins under different physiological conditions, and also indicate two mechanisms by which distinct cytokines can activate the same Stat protein.

The observed interaction between p53 and the oncoproteins encoded by several DNA tumor viruses suggests that these viruses mediate their transforming activities at least in part by altering the normal growth regulatory function of p53. In this study we examined the effect of viral oncoprotein expression on the transcriptional transactivation function of wild‐type p53 in human cells. Plasmids expressing human p53 were cotransfected with either SV40 large T‐antigen or human papillomavirus (HPV) type 16 E6 expression plasmids and assayed for transactivation function using a reporter gene driven by a p53‐responsive promoter containing multiple copies of the consensus p53 DNA binding motif, TGCCT. Both large T‐antigen and E6 were able to inhibit transactivation by wild‐type p53. Furthermore, SV40 T‐antigen mutants that are defective for p53 binding were not able to inhibit transactivation and HPV E6 proteins that were either mutant or derived from non‐oncogenic HPV types and unable to bind p53, had no effect on p53 transactivation. These results demonstrate the physiological relevance of the interaction of SV40 T‐antigen and HPV E6 oncoproteins with p53 in vivo and suggest that the transforming functions of these viral oncoproteins may be linked to their ability to inhibit p53‐mediated transcriptional activation.

The wild-type (wt) p53 protein has transcriptional activation functions which may be linked to its tumor suppressor activity. Many mutant p53 proteins expressed in cancers have lost the ability to function as transcriptional activators and furthermore may inhibit wt p53 function. To study the mechanisms by which mutant forms of p53 have lost their transactivation function and can act in a dominant negative manner, a structure-function analysis of both mutant and engineered truncated forms of p53 was carried out. We show that different mutant p53 proteins found in cancers vary in the ability to inhibit the transcriptional transactivation and specific DNA binding activities of wt human p53. This transdominant effect was mediated through the carboxy-terminal oligomerization region. The role of the transactivation activity in transformation suppression by wt p53 was also examined by constructing an N-terminal deletion mutant lacking the transactivation domain. This mutant was unable to transactivate but could bind specifically to DNA. Although it was impaired in its ability to suppress transformation of primary rat embryo fibroblasts by adenovirus E1A plus activated ras, the N-terminal deletion mutant still had some suppression activity, suggesting that additional functions of p53 may contribute to transformation suppression.Wild-type (wt) p53 is a tumor suppressor protein which has the ability to block cell cycle progression. Mutation of the p53 gene is the most common specific genetic event detected in human cancer and has been found in many different types of human malignancy, including cancers of the colon, liver, breast, lung, brain, and bladder (19,27). In most cases, both alleles of the normal gene for p53 are lost or mutated (2). Many of the mutated p53 genes found in cancers can act as oncogenes in that they are able to cooperate with an activated ras gene to transform primary rodent cells (18). The mechanisms involving negative regulation of cell growth by wt p53, the loss of this property by mutant forms of p53, and the stimulation of cell growth by some forms have not yet been elucidated. The finding that wt p53 has the properties of a sequence-specific transcription factor (14,24,33,44), however, may indicate that p53 affects cellular proliferation by regulating the expression of genes that are in turn involved in cell growth control. The effect of wt p53 on cell growth has been studied in several cell culture systems. wt p53 can induce differentiation of B lymphocytes (47) and induce programmed cell death (apoptosis) in certain cell types (48,61). Further evidence for a role of p53 in cell cycle control came from studies showing that it can induce cell cycle arrest in G1 (6,28,31). The levels of wt p53 increase in response to DNA-damaging agents such as ionizing radiation, leading to G1 arrest. As a result of high levels, p53 may transcriptionally induce the expression of GADD45 (growth arrest and DNA damage protein) by specific binding to a p53-responsive element within the GADD45 gene, resulting in t...

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