Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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There is extensive reprogramming of the ATPase regulators of the 26S proteasome before the programmed elimination of the abdominal intersegmental muscles (ISM) after eclosion in Manduca sexta [1]. This extensive ATPase reprogramming only occurs in ISM which are destined to die and not in flight muscle (FM). The MS73 ATPase also increases in the proleg retractor muscles which die at a developmentally different stage to ISM. The non-ATPase regulator S5a shows a similar increase to the ATPase regulators. We have cloned the Manduca SUG2 ATPase and shown that this ATPase is a component of the 26S proteasome. This ATPase shows a similar increase in concentration to the other ATPases in 26S proteasomes before muscle death. The SUG2 ATPase is also associated with other smaller complexes besides the 26S proteasome which act as activators of the 26S proteasome. Finally, in a yeast two-hybrid genetic screen we have identified a protein in human brain which interacts with the MS73 ATPase (and human S6). The interacting protein contains 6 ankyrin repeats and is co-immunoprecipitated with anti-MS73 antiserum after in vitro transcription/translation. The ankyrin repeat protein may interact with the MS73 ATPase as part of the substrate recognition process by the 26S proteasome. Many proteins degraded by the 26S proteasome contain ankyrin repeats, e.g. IkB and some cyclins: binding through ankyrin repeats to an ATPase regulator may complement protein ubiquitination and S5a binding as recognition signals by the 26S proteasome.
Mol Biol Rep 1997 Mar
PMID:The 26S-proteasome: regulation and substrate recognition. 922 79

CD44 is a family of transmembrane glycoproteins that act mainly as a receptor for hyaluronan. It can also bind some other extracellular matrix ligands (chondroitin sulphate, heparan sulphate, fibronectin, serglycin, osteopontin) with lower affinity. CD44 is encoded by a single gene containing 20 exons, 10 of which (v1-v10) are variant exons inserted by alternative splicing. The standard, ubiquitously expressed isoform of CD44, does not contain sequences encoded by these variant exons. Numerous variant isoforms of CD44 containing different combinations of exons v1-v10 inserted into the extracellular domain can be expressed in proliferating epithelial cells and activated lymphocytes. CD44 plays a significant role in lymphocyte homing. Both alternative splicing and glycosylation influence receptor function of the molecule, usually reducing its affinity to hyaluronan. The cytoplasmic domain of CD44 communicates with the cytoskeleton via ankyrin and proteins belonging to the ezrin-moesin-radixin family. Relatively little is known about the intracellular events following interactions of CD44 with its ligands. Some variant isoforms, especially those containing sequences encoded by v6-v10, are overexpressed in both human and animal neoplasms. In a rat pancreatic adenocarcinoma model one of the variant CD44 isoforms was proved to be determinant in the metastatic process. For some human neoplasms (carcinomas of the digestive tract, non-Hodgkin's lymphomas, thyroid carcinomas, and others) correlations have been made between the particular pattern of CD44 variants produced by neoplastic cells and clinicopathological parameters of tumours, such as grade, stage, presence of metastases, and survival. In vitro studies indicate that modifications of CD44 expression result in different ligand recognition and influence cell motility, invasive properties, and metastatic potential of experimental tumours. Investigation of CD44 neoexpression can be useful both in early cancer diagnosis and in predicting tumour behaviour. It can also contribute to better understanding of molecular mechanisms leading to neoplastic transformation.
Mol Pathol 1997 Apr
PMID:CD44 and the adhesion of neoplastic cells. 923 Nov 52

Doxorubicin (Dox), a cardiotoxic antineoplastic drug, disrupts the cardiac-specific program of gene expression (Kurabayashi, M., Dutta, S., Jeyaseelan, R., and Kedes, L. (1995) Mol. Cell. Biol. 15, 6386-6397; Jeyaseelan, R., Poizat, C., Wu, H. Y., and Kedes, L. (1997) J. Biol. Chem. 272, 5828-5832). To determine whether this drug might interfere with the function of cardiac-specific regulatory pathways, we used a differential display strategy to clone from neonatal rat cardiomyocyte candidate mRNAs that were rapidly sensitive to Dox. We report here the identification of a constitutively expressed, cardiac-restricted, nuclear protein whose mRNA level is exquisitely sensitive to Dox. Hence we have named this protein cardiac adriamycin-responsive protein (CARP). CARP mRNA is present at the earliest stages of cardiac morphogenesis. It was detected by in situ hybridization within the cardiogenic plate of 7. 5-day post coitum (p.c.) embryos, and in 8.5-day p.c. embryos CARP transcripts are present in uniformly high levels in the myocardium. Throughout cardiac development, CARP expression is specific for the myocardium; endocardial cushions and valves exhibit only background levels of signal. Transcript levels persist but gradually decrease in neonatal, 2-week-old, and adult hearts. There were no stages when CARP mRNA could not be detected. The pattern and timing of CARP mRNA expression, including transient expression in the tongue at 14.5 days p.c., coincides with that of Nkx2.5/Csx (a putative homolog of tinman, the Drosophila melanogaster gene responsible for cardiac development). The cloned full-length 1749 nucleotide CARP cDNA encodes a 319-amino acid 40-kDa polypeptide containing five tandem ankyrin repeats. CARP appears to be the rat homolog of a previously reported human single-copy gene (C-193; Chu, W., Burns, D. K., Swerlick, R. A., and Presky, D. H. (1995) J. Biol. Chem. 270, 10236-10245), whose mRNA is inducible by cytokines only in human endothelial cells. CARP appears to function as a negative regulator of cardiac-specific gene expression. Overexpression of CARP in cardiomyocytes suppresses cardiac troponin C and atrial natriuretic factor transcription. Cotransfection experiments in HeLa cells indicate that CARP inhibits Nkx2.5 transactivation of atrial natriuretic factor promoter. When fused to a GAL4 DNA-binding domain, CARP has transcriptional inhibitory properties in noncardiac cells. CARP thus represents the first example of a cardiac-restricted transcriptional regulatory protein that is sensitive to Dox.
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PMID:A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes. 927 41

A novel member of the I kappaB family has been identified as a protein that associated with the p50 subunit of NF-kappaB in a yeast two-hybrid screen. Similar to previously known I kappaB proteins, this member, I kappaB epsilon, has six consecutive ankyrin repeats. I kappaB epsilon mRNA is widely expressed in different human tissues, with highest levels in spleen, testis, and lung. I kappaB epsilon interacts with different NF-kappaB proteins, including p65 (RelA), c-Rel, p50, and p52, in vitro and in vivo and inhibits the DNA-binding activity of both p50-p65 and p50-c-Rel complexes effectively. Endogenous and transfected NF-kappaB (RelA-dependent) transcriptional activation is inhibited by I kappaB epsilon. I kappaB epsilon mRNA is expressed at different levels in specific cell types and is synthesized constitutively in transformed B-cell lines. It also displays differential induction in response to tumor necrosis factor alpha, interleukin-1, or phorbol ester stimulation compared to I kappaB alpha in non-B-cell lines. Therefore, I kappaB epsilon represents a novel I kappaB family member which provides an alternative mechanism for regulation of NF-kappaB-dependent transcription.
Mol Cell Biol 1997 Oct
PMID:A new member of the I kappaB protein family, I kappaB epsilon, inhibits RelA (p65)-mediated NF-kappaB transcription. 931 79

Ankyrins are a multigene family of proteins that function as adapters between the cytoskeleton and trans-membrane proteins, such as ion channels. Previous studies have shown the linkage between ankyrin and ionic transport proteins such as Na+-K+ ATPase, voltage-dependent Na+ channels and Ca2+ channels. In the present study, we have investigated the subcellular distribution of ankyrin and its relationship to the Na+-Ca2+ exchange protein in immature and adult rabbit ventricular myocytes. Isolated single cardiomyocytes from neonatal, juvenile and adult rabbit hearts were examined by immunofluorescence labeling techniques, using antibodies against ankyrin and the Na+-Ca2+ exchanger. We found that in neonatal rabbit cardiac myocytes, ankyrin labeling was mainly present at the Z disk, whereas the Na+-Ca2+ exchanger was only present on the peripheral sarcolemma. At 2 weeks of age, ankyrin labeling was still predominantly observed at the level of the Z disks as well as in the partially developed T-tubules. In the adult cells, however, ankyrin and the Na+-Ca2+ exchanger seem to be co-localized within T-tubules and at the costamere region of the peripheral sarcolemma. Immunogold labeling studies at the higher resolution electron microscopic level using cyrosection tissues of rabbit heart at different ages confirm these findings. These results indicate that the distribution pattern of ankyrin and the Na+-Ca2+ exchanger changes with development in rabbit ventricular myocytes.
J Mol Cell Cardiol 1997 Oct
PMID:Subcellular distribution of ankyrin in developing rabbit heart--relationship to the Na+-Ca2+ exchanger. 934 57

Spectrin isoforms are often segregated within specialized plasma membrane subdomains where they are thought to contribute to the development of cell surface polarity. It was previously shown that ankyrin and beta spectrin are recruited to sites of cell-cell contact in Drosophila S2 cells expressing the homophilic adhesion molecule neuroglian. Here, we show that neuroglian has no apparent effect on a second spectrin isoform (alpha beta H), which is constitutively associated with the plasma membrane in S2 cells. Another membrane marker, the Na,K-ATPase, codistributes with ankyrin and alpha beta spectrin at sites of neuroglian-mediated contact. The distributions of these markers in epithelial cells in vivo are consistent with the order of events observed in S2 cells. Neuroglian, ankyrin, alpha beta spectrin, and the Na,K-ATPase colocalize at the lateral domain of salivary gland cells. In contrast, alpha beta H spectrin is sorted to the apical domain of salivary gland and somatic follicle cells. Thus, the two spectrin isoforms respond independently to positional cues at the cell surface: in one case an apically sorted receptor and in the other case a locally activated cell-cell adhesion molecule. The results support a model in which the membrane skeleton behaves as a transducer of positional information within cells.
Mol Biol Cell 1997 Oct
PMID:Segregation of two spectrin isoforms: polarized membrane-binding sites direct polarized membrane skeleton assembly. 934 34

IkappaBalpha is a critical regulator of Rel/NF-KB-mediated gene activation. It controls the induction of NF-KB factors by retaining them in the cytoplasm and also functions in the nucleus to terminate the induction process. In this study, we show that IkappaBalpha regulates the transcriptional activity of c-Rel in the nuclear compartment. We also demonstrate that discrete functional domains of IkappaBalpha are responsible for the cytoplasmic and nuclear regulation of c-Rel. We show that the determinants for the cytoplasmic regulation of c-Rel reside in the N-terminal and central ankyrin regions of IkappaBalpha and that the N-terminal domain of IkappaBalpha is required to mask the c-Rel nuclear localization signal. Importantly, IkappaBalpha sequences necessary to regulate c-Rel in the nucleus map to its central ankyrin domain and to a few negatively charged amino acids that immediately follow in the C-terminal IkappaBalpha PEST domain. The mapping of the IkappaBalpha determinants that control the cytoplasmic and nuclear activities of c-Rel to specific regions of the molecule suggests that IkappaBalpha inhibitors could be designed to antagonize Rel/NF-kappaB activity in different subcellular compartments or at defined stages of activation.
Mol Cell Biol 1998 Mar
PMID:Distinct domains of IkappaBalpha regulate c-Rel in the cytoplasm and in the nucleus. 948 36

The ability of the IkappaB alpha protein to sequester dimeric NF-kappaB/Rel proteins in the cytoplasm provides an effective mechanism for regulating the potent transcriptional activation properties of NF-kappaB/Rel family members. IkappaB alpha can also act in the nucleus as a postinduction repressor of NF-kappaB/Rel proteins. The mechanism by which IkappaB alpha enters the nucleus is not known, as IkappaB alpha lacks a discernible classical nuclear localization sequence (NLS). We now report that nuclear localization of IkappaB alpha is mediated by a novel nuclear import sequence within the second ankyrin repeat. Deletion of the second ankyrin repeat or alanine substitution of hydrophobic residues within the second ankyrin repeat disrupts nuclear localization of IkappaB alpha. Furthermore, a region encompassing the second ankyrin repeat of IkappaB alpha is able to function as a discrete nuclear import sequence. The presence of a discrete nuclear import sequence in IkappaB alpha suggests that cytoplasmic sequestration of the NF-kappaB/Rel-IkappaB alpha complex is a consequence of the mutual masking of the NLS within NF-kappaB/Rel proteins and the import sequence within IkappaB alpha. Nuclear import may be a conserved property of ankyrin repeat domains (ARDs), as the ARDs from two other ARD-containing proteins, 53BP2 and GABPbeta, are also able to function as nuclear import sequences. We propose that the IkappaB alpha ankyrin repeats define a novel class of cis-acting nuclear import sequences.
Mol Cell Biol 1998 May
PMID:Nuclear localization of IkappaB alpha is mediated by the second ankyrin repeat: the IkappaB alpha ankyrin repeats define a novel class of cis-acting nuclear import sequences. 956 72

To release transcription factor NF-kappaB into the nucleus, the mammalian IkappaB molecules IkappaB alpha and IkappaB beta are inactivated by phosphorylation and proteolytic degradation. Both proteins contain conserved signal-responsive phosphorylation sites and have conserved ankyrin repeats. To confer specific physiological functions to members of the NF-kappaB/Rel family, the different IkappaB molecules could vary in their specific NF-kappaB/Rel factor binding activities and could respond differently to activation signals. We have demonstrated that both mechanisms apply to differential regulation of NF-kappaB function by IkappaB beta relative to IkappaB alpha. Via alternative RNA processing, human IkappaB beta gives rise to different protein isoforms. IkappaB beta1 and IkappaB beta2, the major forms in human cells, differ in their carboxy-terminal PEST sequences. IkappaB beta2 is the most abundant species in a number of human cell lines tested, whereas IkappaB beta1 is the only form detected in murine cells. These isoforms are indistinguishable in their binding preferences to cellular NF-kappaB/Rel homo- and heterodimers, which are distinct from those of IkappaB alpha, and both are constitutively phosphorylated. In unstimulated B cells, however, IkappaB beta1, but not IkappaB beta2, is found in the nucleus. Furthermore, the two forms differ markedly in their efficiency of proteolytic degradation after stimulation with several inducing agents tested. While IkappaB beta1 is nearly as responsive as IkappaB alpha, indicative of a shared activation mechanism, IkappaB beta2 is only weakly degraded and often not responsive at all. Alternative splicing of the IkappaB beta pre-mRNA may thus provide a means to selectively control the amount of IkappaB beta-bound NF-kappaB heteromers to be released under NF-kappaB stimulating conditions.
Mol Cell Biol 1998 May
PMID:Alternative splicing variants of IkappaB beta establish differential NF-kappaB signal responsiveness in human cells. 956 79

Members of the Rel/NF-kappaB family of transcription factors are related to each other over a region of about 300 amino acids called the Rel Homology Domain (RHD), which governs DNA binding, dimerization, and binding to inhibitor. At the C-terminal end of the RHD, each protein has a nuclear localization signal (NLS). The crystal structures of the p50 and RelA family members show that the RHD consists of two regions: an N-terminal section which contains some of the DNA contacts and a C-terminal section which contains the remaining DNA contacts and controls dimerization. In unstimulated cells, the homo- or heterodimeric Rel/NF-kappaB proteins are cytoplasmic by virtue of binding to an inhibitor protein (IkappaB) which somehow masks the NLS of each member of the dimer. The IkappaB proteins consist of an ankyrin-repeat-containing domain that is required for binding to dimers and N- and C-terminal domains that are dispensable for binding to most dimers. In this study, we examined the interaction between IkappaB alpha and Rel family homodimers by mutational analysis. We show that (i) the dimerization regions of p50, RelA, and c-Rel are sufficient for binding to IkappaB alpha, (ii) the NLSs of RelA and c-Rel are not required for binding to IkappaB alpha but do stabilize the interaction, (iii) the NLS of p50 is required for binding to IkappaB alpha, (iv) only certain residues within the p50 NLS are required for binding, and (v) in a p50-IkappaB alpha complex or a c-Rel-IkappaB alpha complex, the N terminus of IkappaB alpha either directly or indirectly masks one or both of the dimer NLSs.
Mol Cell Biol 1998 May
PMID:The N-terminal domain of IkappaB alpha masks the nuclear localization signal(s) of p50 and c-Rel homodimers. 956 83


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