It has been proposed that JNK-interacting proteins (JIP) facilitate mixed lineage kinase-dependent signal transduction to JNK by aggregating the three components of a JNK module. A new model for the assembly and regulation of these modules is proposed based on several observations. First, arti®cially induced dimerization of dual leucine zipper-bearing kinase (DLK) con®rmed that DLK dimerization is suf®cient to induce DLK activation. Secondly, under basal conditions, DLK associated with JIP is held in a monomeric, unphosphorylated and catalytically inactive state. Thirdly, JNK recruitment to JIP coincided with signi®cantly decreased af®nity of JIP and DLK. JNK promoted the dimerization, phosphorylation and activation of JIP-associated DLK. Similarly, treatment of cells with okadaic acid inhibited DLK association with JIP and resulted in DLK dimerization in the presence of JIP. In summary, JIP maintains DLK in a monomeric, unphosphorylated, inactive state. Upon stimulation, JNK±JIP binding af®nity increases while JIP±DLK interaction af®nity is attenuated. Dissociation of DLK from JIP results in subsequent DLK dimerization, autophosphorylation and module activation. Evidence is provided that this model holds for other MLK-dependent JNK modules.
Sixty-nine strains of Vibrio cholerae O1 isolated at different times were analysed to investigate if there were any differences among the O1 strains isolated before, during and after the advent of the O139 serogroup. Of the 69 O1 strains examined, 68 belonged to the Ogawa serotype while one belonged to the Inaba serotype. With the exception of one strain all other strains of V. cholerae O1 belonged to the eltor biotype. A single O1 strain isolated before the emergence of the O139 serogroup could not be classified as either eltor or classical biotype because it was resistant to both classical and eltor specific bacteriophages. Marked variations in the susceptibility to antibiotics of V. cholerae O1 isolated during the different periods were observed. In addition, strains of V. cholerae isolated after the epidemic of serogroup O139 in Calcutta showed an expanding R-type with resistance to a variety of drugs as compared to the O1 strains isolated before the advent of the O139 serogroup. From this study, it is clear that there is a substantial mobility in genetic elements of V. cholerae O1 which necessitates a continuous monitoring to keep abreast of the changing traits of the etiologic agent of cholera.
Summary. Four lines of evidence suggest that the recent outbreak strains of Vibrio cholerae 0139 could have emerged from serogroup 0 1 strains typified by isolates MOl and M0477 described in this paper, which are neither truly classical nor truly El Tor in their biotype attributes. Firstly, like all 0139 isolates, these 0 1 strains, isolated in Madras during and before the 0139 outbreak, were resistant not only to polymyxin B but also to all biotypespecific choleraphages, i.e. classical phage (Dl49 and El Tor phages e4 and e5. Secondly, the restriction fragment pattern (RFP) polymorphism displayed by these strains for the cholera toxin (ctx) gene, were identical with those produced by 0139 isolates but were different from those of 0 1 type strains, namely V. cholerae 569B (classical) and V. cholerae MAK757 (El Tor). Thirdly, all the 0139 isolates and the two 0 1 isolates carried an identical large number of copies of cholera toxin gene in their chromosomes. Finally, the outer-membrane protein profiles of strains MO 1 and M0477 were identical to those of 0 139 isolates but were different from those displayed by strains 569B and MAK757.
A temperate bacteriophage isolated from Vibrio cholerae O139, the new epidemic strain of cholera, was found to have a polyhedral head 65 nm in diameter and a rigid contractile tail 120 nm in length. The phage chromosome was a double-stranded DNA of 35 kb, with unique cohesive ends and had a G + C content of 58.8%. A restriction map of the phage DNA was constructed using the restriction endonucleases AvaI and BstEII. The phage, whose presence could be detected in nine out of 13 V. cholerae O139 isolates tested, was found to have identical chromosomal integration sites in all the strains. The phage attachment site (attP) was found to be located very close to one end of the genome.
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