Edited by Xiao-Fan WangTransforming growth factor-␤ (TGF-␤) signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Existing data have shown the association and coordination between STATs and SMADs in mediating TGF-␤ functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGF␤RI binding protein and is absolutely required for phosphorylation of STATs in a SMAD-independent manner within minutes of TGF-␤ stimulation. Following the activation of SMADs, TGF-␤ also induces a second phase of STAT phosphorylation that requires SMADs, de novo protein synthesis, and contribution from JAK1. Our global gene expression profiling indicates that the non-SMAD JAK1/STAT pathway is essential for the expression of a subset of TGF-␤ target genes in hepatic stellate cells, and the cooperation between the JAK1-STAT3 and SMAD pathways is critical to the roles of TGF-␤ in liver fibrosis.

A comparative analysis of three Epstein-Barr virus DNAs from American patients with infectious mononucleosis (B95-8, Cherry, and Lamont) and four Epstein-Barr virus DNAs from African patients with Burkitt lymphoma (AG876, W91, Raji, and P3HR-1) indicated that the usual format of Epstein-Barr virus DNA includes a variable number of direct repeats of a 0.35 X 10(6)-dalton sequence (TR) at both ends of the DNA, a 9 X 10(6)-dalton sequence of largely unique DNA (Us), a variable number of repeats of a 2 X 10(6)-dalton sequence (IR), and a 89 X 10(6)-dalton sequence of largely unique DNA (UL). Within UL there was homology between DNA at 26 X 10(6) to 28 X 10(6) daltons and DNA at 93 X 10(6) to 95 X 10(6) daltons. The relative sequence order (TR, US, IR, UL, TR) did not vary among "standard" Epstein-Barr virus DNA molecules of each isolate. B95-8 DNA had an unusual deletion extending from 91 X 10(6) to 100 X 10(6) daltons, and P3HR-1 DNA had an unusual deletion extending from 23.5 X 10(6) to 26 X 10(6) daltons. There was sufficient variability among the EcoRI and BamHI fragments of the DNAs to identify each isolate specifically. However, we discerned no distinguishing features for the two geographic or pathogenic origins of the seven isolates. Three intracellular DNAs (Raji, Lamont, and Cherry) and one virion DNA (P3HR-1) were heterogenous in molecular organization and had subpopulations of rearranged or defective molecules. Some regions, particularly 59 X 10(6) to 63 X 10(6) daltons and sequences around TR, frequently participated in rearrangements. Restriction endonuclease maps of the standard and rearranged DNAs of the seven isolates are presented.

Calcium binding to the thin filament protein troponin is required for cardiac and skeletal muscles to contract, and several studies indicate that this regulation involves shifting the tropomyosin position on the actin filament. When the regulatory sites of troponin do not have bound Ca 2ϩ , tropomyosin is located on the actin outer domain. In this position tropomyosin sterically interferes with much more of the myosin-binding site than it does in the presence of Ca 2ϩ , and therefore contraction is inhibited at low Ca 2ϩ concentrations. This regulatory scheme is supported by three-dimensional helical reconstructions of thin filaments examined by electron microscopy with negative staining (1, 2) or unstained in vitreous ice (3), and by modeling of x-ray diffraction patterns of muscle (4). Furthermore, it is consistent with the solution kinetics of myosin S1-thin filament binding in the absence of ATP (5). However, it is unclear how troponin affects the position of tropomyosin on actin, and more generally the inhibitory action of troponin is not well understood at a structural level, as opposed to better understandings of tropomyosin.Troponin consists of a relatively globular domain (including TnI 1 and TnC) and an elongated tail region, the NH 2 terminus of TnT (6, 7). The inhibitory actions of troponin have long been attributed to the TnI subunit. Skeletal muscle TnI inhibits the actin-myosin ATPase rate in the absence of the other troponin subunits TnC and TnT (8 -10), and this effect requires lower TnI concentrations in the presence rather than in the absence of tropomyosin (11). Cardiac TnI has similar properties, although the inhibition is less effective (12-14). The inhibitory effects of skeletal muscle TnI can be mimicked by the so-called inhibitory peptide, residues 96 -116 (10, 15), or identically by the corresponding cardiac peptide (14). The reversal of inhibition is related to Ca 2ϩ -dependent TnI-TnC interactions, elucidated in part at the atomic level (16). An additional TnI region, approximately 130 -150 residues, has also been implicated in inhibition (17)(18)(19). These and other data are consistent with an inhibitory mechanism consisting primarily of a TnI-actin interaction that is reversed by Ca 2ϩ , i.e. a localized actin-troponin interaction tethers the much longer tropomyosin on the actin outer domain in the absence, but not in the presence, of Ca 2ϩ . Indeed, our own electron microscope results show that Ca 2ϩ causes a decrease in troponin density in contact with actin (20). However, no high resolution data exists for these interactions, or for the assembled thin filament, and it remains possible that other mechanisms are also important for regulation and for determining the shifting positions of tropomyosin on the actin surface.This report describes new and unexpected attributes of the troponin tail, i.e. the NH 2 terminus of TnT. In the absence of all other portions of troponin, including TnI, cardiac TnT-(1-153) inhibited the interaction of myosin with actin-tropomyosin filaments. Helica...

The entire Epstein-Barr virus genome is integrated into Burkitt tumor cell DNA at the terminal direct repeat sequence of the virus. There is no homology between the GC-rich (G, guanine; C, cytosine) terminal repeat and the AT-rich (A, adenine; T, thymine) cell sequences with which it has recombined. More than 15 kilobases of cell DNA have been deleted and 236 base pairs are duplicated at one virus-cell junction site.