Three SUMO (small ubiquitin-related modifier) genes have been identified in humans, which tag proteins to modulate subcellular localization and/or enhance protein stability and activity. We report the identification of a novel intronless SUMO gene, SUMO-4, that encodes a 95-amino acid protein having an 86% amino acid homology with SUMO-2. In contrast to SUMO-2, which is highly expressed in all of the tissues examined, SUMO-4 mRNA was detected mainly in the kidney. A single nucleotide polymorphism was detected in SUMO-4, substituting a highly conserved methionine with a valine residue (M55V). In HepG2 (liver carcinoma) cells transiently transfected with SUMO-4 expression vectors, Met-55 was associated with the elevated levels of activated heat shock factor transcription factors as compared with Val-55, whereas the levels of NF-B were suppressed to an identical degree. The SUMO-4M (Met) variant is associated with type I diabetes mellitus susceptibility in families (p ‫؍‬ 4.0 ؋ 10 ؊4 ), suggesting that it may be involved in the pathogenesis of type I diabetes. SUMO-11 is involved in the post-translational modification of cellular proteins and regulates various cellular processes such as nuclear transport, oncogenesis, stress response, inflammation, and the response to viral infection (1). SUMO-1 is related to ubiquitin, and although both share only an 18% sequence homology, they have a similar three-dimensional structure (1). In contrast to ubiquitin, which tags proteins for degradation, SUMO-1 seems to enhance protein stability and modulate the subcellular localization. The list of mammalian proteins, which are known to be sumoylated, is growing continually and includes RAN GTPase-activating protein 1 (nuclear import) (2), IB␣ (NF-B inhibition) (3), c-Jun (transcription factor), p53 (tumor suppressor) (4), GLUT1 and GLUT4 (glucose transport) (5), heat shock transcription factors 1 and 2 (HSF1 and 2) (6, 7), and FAS/APO-1 (cell death domain/ apoptosis) (8).SUMO-1 is expressed initially as an inactive precursor of 101 amino acids. A C-terminal proteolytic event exposes two glycine residues at the C terminus that are involved in the formation of a peptide bond with the ⑀-amino group of a lysine residue of a target protein. The activating enzymes E1 (AOS1 and UBA2) and the conjugating enzyme E2 (UBC9) are required for sumoylation in vitro (1). In vivo, an additional enzyme E3 is required for efficient sumoylation (9). The E2 enzyme, UBC9, is specific for sumoylation, and recently, two additional SUMO family members have been identified based on the interaction with UBC9, SUMO-2, and SUMO-3 (10, 11). SUMO-1 shares a 48% identity with SUMO-2 and a 46% with SUMO-3. Very little is known regarding the functions of SUMO-2 and SUMO-3. However, SUMO-2 and SUMO-3 contain a consensus SUMO modification site (Fig. 1), which enables self-sumoylation and the formation of polymeric chains (11), in contrast to SUMO-1. Thus, SUMO-2 and SUMO-3 may have different roles in cellular functions.Here, we identify and characterize a novel fou...

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Pancreatic amylase messenger RNA progressively decreases in rats rendered diabetic with streptozotocin. Insulin reverses this effect, inducing a selective decrease in amylase messenger RNA in the pancreas. Parotid amylase messenger RNA is not significantly affected by either diabetes or insulin.

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The human HLA-D histocompatibility region encodes class II antigens each of which consists of two polypeptide chains (alpha and beta) inserted in the plasma membrane. These molecules are implicated in the regulation of the immune response but several human diseases are also found to be associated with certain HLA-DR antigens. The occurrence of insulin-dependent (type I) diabetes (IDDM) is strongly associated with HLA-DR3 and/or 4 (ref. 5). The class II antigens, however, show a marked genetic polymorphism associated with the beta-chains which seem, from hybridization studies, to be encoded by several genes. We have therefore used the beta-chain cDNA probe, pDR-beta-1 (refs 8, 10) to test whether there are differences in hybridization pattern between DNA from healthy individuals and diabetic patients, after digestion with restriction endonucleases. Among the HLA-DR 4 and 3/4 individuals, the IDDM patients showed an increased frequency of a PstI 18 kilobase (kb) fragment. A BamHI 3.7 kb fragment, frequent among controls (30-40%), was rarely detected in the IDDM patients (0-2%). These differences may be related to susceptibility to develop the disease.