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排序方式: 共有10000条查询结果,搜索用时 15 毫秒
921.
922.
Steinbusch LK Schwenk RW Ouwens DM Diamant M Glatz JF Luiken JJ 《Cellular and molecular life sciences : CMLS》2011,68(15):2525-2538
Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose
transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored
in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well
as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly
affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized
at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate
uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences
in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved
in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both
GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking
components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development
of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy. 相似文献
923.
924.
Thomae AW Baltin J Pich D Deutsch MJ Ravasz M Zeller K Gossen M Hammerschmidt W Schepers A 《Cellular and molecular life sciences : CMLS》2011,68(22):3741-3756
In eukaryotes, binding of the six-subunit origin recognition complex (ORC) to DNA provides an interactive platform for the
sequential assembly of pre-replicative complexes. This process licenses replication origins competent for the subsequent initiation
step. Here, we analyze the contribution of human Orc6, the smallest subunit of ORC, to DNA binding and pre-replicative complex
formation. We show that Orc6 not only interacts with Orc1–Orc5 but also with the initiation factor Cdc6. Biochemical and imaging
experiments reveal that this interaction is required for licensing DNA replication competent. Furthermore, we demonstrate
that Orc6 contributes to the interaction of ORC with the chaperone protein HMGA1a (high mobility group protein A1a). Binding
of human ORC to replication origins is not specified at the level of DNA sequence and the functional organization of origins
is poorly understood. We have identified HMGA1a as one factor that might direct ORC to AT-rich heterochromatic regions. The
systematic analysis of the interaction between ORC and HMGA1a revealed that Orc6 interacts with the acidic C-terminus of HMGA1a
and also with its AT-hooks. Both domains support autonomous replication if targeted to DNA templates. As such, Orc6 functions
at different stages of the replication initiation process. Orc6 can interact with ORC chaperone proteins such as HMGA1a to
facilitate chromatin binding of ORC and is also an essential factor for pre-RC formation. 相似文献
925.
Pan Q Qiao F Gao C Norman B Optican L Zelenka PS 《Cellular and molecular life sciences : CMLS》2011,68(20):3425-3436
The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In
normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent
ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work
has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75).
Here we show that this phosphorylation promotes the ubiquitin-dependent degradation of Src, thus restricting the availability
of active Src. We demonstrate that Src(S75) phosphorylation occurs in vivo in epithelial cells, and like ubiquitinylation,
is associated only with active Src. Preventing Cdk5-dependent phosphorylation of Src(S75), by site-specific mutation of S75
or by Cdk5 inhibition or suppression, increases Src(Y419) phosphorylation and kinase activity, resulting in Src-dependent
cytoskeletal changes. In transfected cells, ubiquitinylation of Src(S75A) is about 35% that of wild-type Src-V5, and its half-life
is approximately 2.5-fold greater. Cdk5 suppression leads to a comparable decrease in the ubiquitinylation of endogenous Src
and a similar increase in Src stability. Together, these findings demonstrate that Cdk5-dependent phosphorylation of Src(S75)
is a physiologically significant mechanism of regulating intracellular Src activity. 相似文献
926.
927.
928.
Ververis K Rodd AL Tang MM El-Osta A Karagiannis TC 《Cellular and molecular life sciences : CMLS》2011,68(24):4101-4114
Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid
(Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that
histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies
such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies,
involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified
that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in
cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase
inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes.
Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum histone deacetylase inhibitors
tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained
nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight
the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination
therapies for cancer. 相似文献
929.
The maintenance of mucosal barrier equilibrium in the intestine requires a delicate and dynamic balance between enterocyte
loss by apoptosis and the generation of new cells by proliferation from stem cell precursors at the base of the intestinal
crypts. When the balance shifts towards either excessive or insufficient apoptosis, a broad range of gastrointestinal diseases
can manifest. Recent work from a variety of laboratories has provided evidence in support of a role for receptors of the innate
immune system, including Toll-like receptors 2, 4, and 9 as well as the intracellular pathogen recognition receptor NOD2/CARD15,
in the initiation of enterocyte apoptosis. The subsequent induction of enterocyte apoptosis in response to the activation
of these innate immune receptors plays a key role in the development of various intestinal diseases, including necrotizing
enterocolitis, Crohn’s disease, ulcerative colitis, and intestinal cancer. This review will detail the regulatory pathways
that govern enterocyte apoptosis, and will explore the role of the innate immune system in the induction of enterocyte apoptosis
in gastrointestinal disease. 相似文献
930.
Lubka-Pathak M Shah AA Gallozzi M Müller M Zimmermann U Löwenheim H Pfister M Knipper M Blin N Schimmang T 《Cellular and molecular life sciences : CMLS》2011,68(16):2739-2749