SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4.

NF kappa B is an important transcriptional regulator of multiple pro-inflammatory genes. In non-stimulated cells NF kappa B is anchored in the cytoplasm via the inhibitory protein I kappa B alpha. Following exposure to diverse pro-inflammatory signals (e.

The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro.

Ubiquitin-mediated proteolysis has a central role in controlling the intracellular levels of several important regulatory molecules such as cyclins, CKIs, p53, and IkappaBalpha. Many diverse proinflammatory signals lead to the specific phosphorylation and subsequent ubiquitin-mediated destruction of the NF-kappaB inhibitor protein IkappaBalpha. Substrate specificity in ubiquitination reactions is, in large part, mediated by the specific association of the E3-ubiquitin ligases with their substrates.

Antisense targeting of E6AP elevates p53 in HPV-infected cells but not in normal cells.

Invasive cervical cancer is very highly correlated with the presence of high-risk human papillomavirus (HPV) types 16 and 18. Two viral proteins, E6 and E7, act in concert to subvert growth control of infected cells by inactivating the tumor suppressor proteins, p53 and Rb, respectively. E6 is thought to abrogate p53 function by stimulating its degradation via ubiquitin-mediated proteolysis in a reaction requiring E6AP (E6-Associated Protein).

Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer.

Background: Mutations in a germ-line allele of the BRCA1 gene contribute to the familial breast cancer syndrome. However, the prevalence of these mutations is unknown in women with breast cancer who do not have the features of this familial syndrome. We sought BRCA1 mutations in women who were given a diagnosis of breast cancer at an early age, because early onset is characteristic of a genetic predisposition to cancer.

Identification of an essential acidic residue in Cdc25 protein phosphatase and a general three-dimensional model for a core region in protein phosphatases.

The reaction mechanism of protein tyrosine phosphatases (PTPases) and dual-specificity protein phosphatases is thought to involve a catalytic aspartic acid residue. This residue was recently identified by site-directed mutagenesis in Yersinia PTPase, VHR protein phosphatase, and bovine low molecular weight protein phosphatase. Herein we identify aspartic acid 383 as a potential candidate for the catalytic acid in human Cdc25A protein phosphatase, using sequence alignment, structural information, and site-directed mutagenesis.

Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27.

The p27 mammalian cell cycle protein is an inhibitor of cyclin-dependent kinases. Both in vivo and in vitro, p27 was found to be degraded by the ubiquitin-proteasome pathway. The human ubiquitin-conjugating enzymes Ubc2 and Ubc3 were specifically involved in the ubiquitination of p27.

Reconstitution of p53-ubiquitinylation reactions from purified components: the role of human ubiquitin-conjugating enzyme UBC4 and E6-associated protein (E6AP).

The E6 protein of the high-risk human papillomaviruses inactivates the tumor suppressor protein p53 by stimulating its ubiquitinylation and subsequent degradation. Ubiquitinylation is a multistep process involving a ubiquitin-activating enzyme, one of many distinct ubiquitin-conjugating enzymes, and in certain cases, a ubiquitin ligase. In human papillomavirus-infected cells, E6 and the E6-associated protein are thought to act as a ubiquitin-protein ligase in the ubiquitinylation of p53.

Evidence that the SRY protein is encoded by a single exon on the human Y chromosome.

To facilitate studies of the SRY gene, a 4741-bp portion of the sex-determining region of the human Y chromosome was sequenced and characterized. Two RNAs were found to hybridize to this genomic segment, one transcript deriving from SRY and the second cross-hybridizing to a pseudogene located 2.5 kb 5' of the SRY open reading frame (ORF).

The human Y chromosome: a 43-interval map based on naturally occurring deletions.

A deletion map of the human Y chromosome was constructed by testing 96 individuals with partial Y chromosomes for the presence or absence of many DNA loci. The individuals studied included XX males, XY females, and persons in whom chromosome banding had revealed translocated, deleted, isodicentric, or ring Y chromosomes. Most of the 132 Y chromosomal loci mapped were sequence-tagged sites, detected by means of the polymerase chain reaction.

Rps4 maps near the inactivation center on the mouse X chromosome.

RPS4Y, a Y-linked gene in humans, appears to encode an isoform of ribosomal protein S4. A homologous locus on the human X chromosome, RPS4X, lies close to the X-inactivation center but fails to undergo X-inactivation. We have isolated a genomic clone from the mouse Rps4 locus, the homolog of human RPS4X.

Inactivation of the Rps4 gene on the mouse X chromosome.

The human RPS4X and RPS4Y genes, located on the X and Y chromosomes, appear to encode isoforms of ribosomal protein S4. Haploinsufficiency of these genes may contribute to the human phenotype known as Turner syndrome. Although RPS4X maps near the X-inactivation center, the gene is expressed on inactive human X chromosomes.

Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome.

We have isolated two genes on the human sex chromosomes, one on the Y and one on the X, that appear to encode isoforms of ribosomal protein S4. These predicted RPS4Y and RPS4X proteins differ at 19 of 263 amino acids. Both genes are widely transcribed in human tissues, suggesting that the ribosomes of human males and females are structurally distinct.

Putative transcription activator with alternative isoforms encoded by human ZFX gene.

The ZFY gene in the sex-determining region of the human Y chromosome encodes a protein with 13 zinc fingers, and may determine whether an embryo develops as a male or female. ZFX, a related gene on the human X chromosome, may also function in sex determination; it encodes a protein with a very similar zinc-finger domain and escapes X inactivation. ZFY and ZFX diverged from a common ancestral gene before the radiation of placental mammals, and retain a similar genomic organization.

ZFX has a gene structure similar to ZFY, the putative human sex determinant, and escapes X inactivation.

The ZFX gene on the human X chromosome is structurally similar to the ZFY gene, which may constitute the sex-determining signal on the human Y chromosome. ZFY and ZFX diverged from a common ancestral gene, as evidenced by similarities in their intron/exon organization and exon DNA sequences. The carboxy-terminal exons of ZFY and ZFX both encode 13 zinc fingers; 383 of 393 amino acid residues are identical, and there are no insertions or deletions.

Sporotrichosis in the Orinoco river basin of Venezuela and Colombia.

Six cases of sporotrichosis from the Orinoco river basin of Venezuela and Colombia are described; two are of the localized cutaneous type and four are lymphocutaneous. Diagnosis was based on the patient's clinical history and mycological culture. Epidemiology and distinctive cultural habits of the patients are discussed in connection with disease etiology.