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B McCright

Publications and source records attributed to B McCright.

7 recordsLinked to original sources
PubMed2001

Mouse CLK-1 is imported into mitochondria by an unusual process that requires a leader sequence but no membrane potential.

clk-1 has been identified and characterized in the nematode Caenorhabditis elegans as a gene that affects the rates, regularity, and synchrony of physiological processes. The CLK-1 protein is mitochondrial and is required for ubiquinone biosynthesis in yeast and in worms, but its biochemical function remains unclear. We have studied the expression of murine mclk1 in a variety of tissues, and we find that the pattern of mclk1 mRNA accumulation closely resembles that of mitochondrial genes involved in oxidative phosphorylation. The pattern of protein accumulation, however, is sharply distinct in some tissues; mCLK1 appears relatively enriched in the gut and depleted in the nervous tissue. We also show that mCLK1 is synthesized as a preprotein that is imported into the mitochondrial matrix, where a leader sequence is cleaved off and the protein becomes loosely associated with the inner membrane. However, in contrast to all known mitochondrial proteins that contain a cleavable pre-sequence, the import of mCLK1 does not require a mitochondrial membrane potential.

Amino Acid Sequence↗
PubMed2001

The C. elegans maternal-effect gene clk-2 is essential for embryonic development, encodes a protein homologous to yeast Tel2p and affects telomere length.

The Caenorhabditis elegans maternal-effect clk genes are involved in the temporal control of development and behavior. We report the genetic and molecular characterization of clk-2. A temperature-sensitive mutation in the gene clk-2 affects embryonic and post-embryonic development, reproduction, and rhythmic behaviors. Yet, virtually all phenotypes are fully maternally rescued. Embryonic development strictly requires the activity of maternal clk-2 during a narrow time window between oocyte maturation and the two- to four-cell embryonic stage. Positional cloning of clk-2 reveals that it encodes a protein homologous to S. cerevisiae Tel2p. In yeast, the gene TEL2 regulates telomere length and participates in gene silencing at subtelomeric regions. In C. elegans, clk-2 mutants have elongated telomeres, and clk-2 overexpression can lead to telomere shortening. Tel2p has been reported to bind to telomeric DNA repeats in vitro. However, we find that a functional CLK-2::GFP fusion protein is cytoplasmic in worms. We discuss how the phenotype of clk-2 mutants could be the result of altered patterns of gene expression.

Amino Acid Sequence↗
PubMed2001

Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation.

The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the in vivo role of the Notch2 gene, we constructed a targeted mutation, Notch2(del1). Unexpectedly, we found that alternative splicing of the Notch2(del1) mutant allele leads to the production of two different in-frame transcripts that delete either one or two EGF repeats of the Notch2 protein, suggesting that this allele is a hypomorphic Notch2 mutation. Mice homozygous for the Notch2(del1) mutation died perinatally from defects in glomerular development in the kidney. Notch2(del1)/Notch2(del1 )mutant kidneys were hypoplastic and mutant glomeruli lacked a normal capillary tuft. The Notch ligand encoded by the Jag1 gene was expressed in developing glomeruli in cells adjacent to Notch2-expressing cells. We show that mice heterozygous for both the Notch2(del1) and Jag1(dDSL) mutations exhibit a glomerular defect similar to, but less severe than, that of Notch2(del1)/Notch2(del1 )homozygotes. The co-localization and genetic interaction of Jag1 and Notch2 imply that this ligand and receptor physically interact, forming part of the signal transduction pathway required for glomerular differentiation and patterning. Notch2(del1)/Notch2(del1 )homozygotes also display myocardial hypoplasia, edema and hyperplasia of cells associated with the hyaloid vasculature of the eye. These data identify novel developmental roles for Notch2 in kidney, heart and eye development.

Alleles↗
PubMed1996

The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm.

Protein phosphatase 2A is a heterotrimeric protein serine/threonine phosphatase consisting of a 36-kDa catalytic C subunit, a 65-kDa structural A subunit, and a variable regulatory B subunit. The B subunits determine the substrate specificity of the enzyme. There have been three families of cellular B subunits identified to date: B55, B56 (B'), and PR72/130. We have now cloned five genes encoding human B56 isoforms. Polypeptides encoded by all but one splice variant (B56gamma1) are phosphoproteins, as shown by mobility shift after treatment with alkaline phosphatase and metabolic labeling with [32P]phosphate. All labeled isoforms contain solely phosphoserine. Indirect immunofluorescence microscopy demonstrates distinct patterns of intracellular targeting by different B56 isoforms. Specifically, B56alpha, B56beta, and B56epsilon complexed with the protein phosphatase 2A A and C subunits localize to the cytoplasm, whereas B56delta, B56gamma1, and B56gamma3 are concentrated in the nucleus. Two isoforms (B56beta and B56delta) are highly expressed in adult brain; here we show that mRNA for these isoforms increases severalfold when neuroblastoma cell lines are induced to differentiate by retinoic acid treatment. These studies demonstrate an increasing diversity of regulatory mechanisms to control the activity of this key intracellular protein phosphatase and suggest distinct functions for isoforms targeted to different intracellular locations.

Adult↗
PubMed1996

Assignment of human protein phosphatase 2A regulatory subunit genes b56alpha, b56beta, b56gamma, b56delta, and b56epsilon (PPP2R5A-PPP2R5E), highly expressed in muscle and brain, to chromosome regions 1q41, 11q12, 3p21, 6p21.1, and 7p11.2 --> p12.

The activity of the major intracellular protein phosphatase, protein phosphatase 2A (PP2A), is determined by the nature of the associated regulatory subunit. A new family of human PP2A regulatory subunits has recently been identified. Three of these subunits, B56beta, B56delta, and B56epsilon, are most highly expressed in brain, while the B56alpha and B56gamma isoforms are highly expressed in cardiac and skeletal muscle. Genes PPP2R5A-PPP2R5E encoding the phosphatase regulatory proteins B56alpha, B56beta, B56gamma, B56delta, and B56epsilon have now been mapped by fluorescence in situ hybridization to chromosome regions 1q41, 11q12, 3p21, 6p21.1, and 7p11.2 --> p12, respectively.

Brain Chemistry↗
PubMed1995

Identification of a new family of protein phosphatase 2A regulatory subunits.

Protein phosphatase 2A (PP2A) is a major intracellular protein phosphatase that regulates multiple aspects of cell growth and metabolism. The ability of this widely distributed heterotrimeric enzyme to act on a diverse array of substrates is largely controlled by the nature of its regulatory B subunit. Only two gene families encoding endogenous B subunits have been cloned to date, although the existence of several additional regulatory subunits is likely. We have identified by two-hybrid interaction a new human gene family encoding PP2A B subunits. This family, denoted B56, contains three distinct genes, one of which is differentially spliced. B56 polypeptides co-immunoprecipitate with PP2A A and C subunits and with an okadaic acid-inhibitable, heparin-stimulated phosphatase activity. The three B56 family members are 70% identical to each other but share no obvious homology with previously identified B subunits. These phosphatase regulators are differentially expressed, with B56 alpha and B56 gamma highly expressed in heart and skeletal muscle and B56 beta highly expressed in brain. The identification of this novel phosphatase regulator gene family will facilitate future studies on the control of protein dephosphorylation and the role of PP2A in cellular function.

Alternative Splicing↗