Biomedical subjects

Caretha L Creasy

Publications and source records attributed to Caretha L Creasy.

3 recordsLinked to original sources

PubMed2004

The yeast Pho80-Pho85 cyclin-CDK complex has multiple substrates.

The Pho85-Pho80 cyclin-CDK (cyclin-dependent protein kinase) complex of Saccharomyces cerevisiae functions as a key regulator of the phosphate-repressible acid phosphatase system. We have further characterized the Pho85-Pho80 kinase complex and identified the Pho80 cyclin subunit and the Pho81 CDK inhibitor as substrates of the Pho85 protein kinase. The phosphorylation sites within Pho80 have been identified at Ser234 and Ser267. Of the two sites, phosphorylation of Ser234 is required for Pho80 function, to form an active kinase complex and repress acid phosphatase expression. Evidence suggests that the activity of Pho81 is regulated by a post-translational modification and therefore that Pho85-mediated phosphorylation of Pho81 may alter its ability to function as a CDK inhibitor. Thus, the control of acid phosphatase expression involves the phosphorylation of several of the regulatory components of the system.

Cyclin-Dependent Kinases↗

PubMed2004

Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice.

The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster.

Animals↗

PubMed2001

The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif.

The inhibitor-of-apoptosis proteins (IAPs) play a critical role in the regulation of apoptosis by binding and inhibiting caspases. Reaper family proteins and Smac/DIABLO use a conserved amino-terminal sequence to bind to IAPs in flies and mammals, respectively, blocking their ability to inhibit caspases and thus promoting apoptosis. Here we have identified the serine protease Omi/HtrA2 as a second mammalian XIAP-binding protein with a Reaper-like motif. This protease autoprocesses to form a protein with amino-terminal homology to Smac/DIABLO and Reaper family proteins. Full-length Omi/HtrA2 is localized to mitochondria but fails to interact with XIAP. Mitochondria also contain processed Omi/HtrA2, which, following apoptotic insult, translocates to the cytosol, where it interacts with XIAP. Overexpression of Omi/HtrA2 sensitizes cells to apoptosis, and its removal by RNA interference reduces cell death. Omi/HtrA2 thus extends the set of mammalian proteins with Reaper-like function that are released from the mitochondria during apoptosis.

Amino Acid Motifs↗