A subset of growth hormone-secreting human pituitary tumours carries somatic mutations that inhibit GTPase activity of a G protein alpha chain, alpha(s). The resulting activation of adenylyl cyclase bypasses the cells' normal requirement for trophic hormone. Amino acids substituted in the putative gsp oncogene identify a domain of G protein alpha-chains required for intrinsic ability to hydrolyse GTP. This domain may serve as a built-in counter-part of the separate GTPase-activating proteins required for GTP hydrolysis by small GTP-binding proteins such as p21ras.
The interleukin-1 (IL-1) family members play an important role in the process of inflammation and host defense. We describe here the identification and characterization of a novel member of the IL-1 family, IL-1HY2. The human IL-1HY2 protein shares significant amino acid sequence similarity (37%) with the IL-1 receptor antagonist and has a predicted three-dimensional structure similar to that of the IL-1 receptor antagonist. The IL-1HY2 gene is located in close proximity to other IL-1 family genes on human chromosome 2, and the genomic organization of the IL-1HY2 gene is highly conserved with other IL-1 family members. IL-1HY2 protein is secreted from mammalian cells, and the purified recombinant IL-1HY2 protein binds soluble IL-1 receptor type I. IL-1HY2 is expressed in human skin, spleen, and tonsil. Immunohistochemical analysis showed that the IL-1HY2 protein is expressed in the basal epithelia of skin and in proliferating B cells of the tonsil. These data suggest that IL-1HY2 is a novel IL-1 family member and that it may participate in a network of IL-1 family members to regulate adapted and innate immune responses.
One or more of three Gi proteins, Gi1-3, mediates hormonal inhibition of adenylyl cyclase. Whether this inhibition is mediated by the alpha or by the beta gamma subunits of Gi proteins is unclear. Mutations inhibiting the intrinsic GTPase activity of another G protein, the stimulatory regulator of adenylyl cyclase (Gs), constitutively activate it by replacing either of two conserved amino acids in its alpha subunit (alpha s). These mutations create the gsp oncogene which is found in human pituitary and thyroid tumours. In a second group of human endocrine tumours, somatic mutations in the alpha subunit of Gi2 replace a residue cognate to one of those affected by gsp mutations. This implies that the mutations convert the alpha i2 gene into a dominantly acting oncogene, called gip2, and that the mutant alpha i2 subunits are constitutively active. We have therefore assessed cyclic AMP accumulation in cultured cells which stably or transiently express exogenous wild-type alpha i2 complementary DNA or either of two mutant alpha i2 cDNAs. The results show that putatively oncogenic mutations in alpha i2 constitutively activate the protein's ability to inhibit cAMP accumulation.
In a recently discovered class of oncogenes, GTPase-inhibiting mutations constitutively activate a subunits of signal-transducing guanine nucleotide-binding proteins (G proteins). Somatic mutations in a subclass of endocrine tumors are found in the arginine-179 codon ofthe a subunit ofGu2 (aj2), creating the putative gip2 oncogene. We have tested the ability ofgip2 to mediate neoplastic transformation of Rat-l and NIH 3T3 fibroblasts in tissue culture. Expression of a mutant aj2 cDNA encoding cysteine in place of arginine-179 (au2-R179C)caused Rat-1 cells to grow to a higher density in monolayer culture, to lose anchorage dependence, and to form tumors when injected subcutaneously into nude mice. In contrast, expression of aj2-R179C failed to alter growth or tumorigenicity of NIH 3T3 cells. We conclude that gip2 is an oncogene, by the criterion that it induces neoplastic transformation of Rat-1 cells. Failure of gip2 to transform NIH 3T3 cells is in keeping with clinical indications that gip2 is a tissue-selective oncogene.Hormone receptors activate heterotrimeric guanine nucleotide-binding proteins (G proteins) by promoting replacement of GDP by GTP in the guanine nucleotide-binding sites of the G proteins' a subunits. Each GTP-bound a subunit then regulates the activity of its specific downstream effector(s) until an intrinsic GTPase activity converts bound GTP to GDP, turning off the a subunit and returning it to its GDP-bound, inactive state. In the a subunit of Gs (as), point mutations (1-4) or cholera toxin-catalyzed covalent modification (5) inhibit this GTPase turnoff mechanism, thereby inducing constitutive activation of adenylyl cyclase, the effector of Gs.Recently discovered mutations in genes for G protein a subunits have revealed an additional class of human oncogenes. As with many other oncogenes, these a subunit mutations presumably constitutively activate mitogenic signaling pathways that are normally regulated by their corresponding protooncogene products. The gsp oncogene results from somatic point mutations that inhibit the GTPase activity of as, causing constitutive activation of adenylyl cyclase. By mimicking mitogenic effects of trophic hormones that normally stimulate cAMP synthesis via Gs-coupled receptors, the gsp oncogene contributes to the growth oftumors derived from pituitary somatotrophs (2, 6-9) and thyroid cells (7).A second putative G protein oncogene, gip2, results from somatic point mutations in the gene for the a subunit of Gi2 (ai2) (7). Three inferences suggest that these a12 mutations create an oncogene: (i) gip2 mutations are found in a substantial proportion (z30%) of a restricted subclass of human tumors-i.e., those derived from the adrenal cortex or from endocrine cells of the ovary (7). (ii) gip2 mutations were found by a method-allele-specific hybridization to tumor DNA-that can only detect clonally expanded alterations in DNA; clonal expansion is a hallmark of neoplasia. (iii) gip2 mutations substitute cysteine or histidine for the arginine residue at positi...
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