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101.
Yoshito Yamashiro Kimiko Takei Masato Umikawa Minoru Oshiro Takahiro Ishikawa Hiroshi Uezato 《Biochemical and biophysical research communications》2010,399(3):365-2106
Cutaneous squamous cell carcinoma (cSCC) results from transformation of epidermal keratinocytes. Invasion of transformed keratinocytes through the basement membrane into the dermis results in invasive cSCC with substantial metastatic potential. To better understand the mechanisms for invasion and metastasis, we compared the protein expression profiles of a non-metastatic transformed mouse keratinocyte line and its metastatic derivative. Keratin 8 (Krt8) and Krt18, not seen in normal keratinocytes, were coexpressed and formed Krt8/18 filaments in the metastatic line. The metastatic line efficiently invaded an artificial basement membrane in vitro owing to the Krt8/18-coexpression, since coexpression of exogenous Krt8/18 in the non-invasive parental line conferred invasiveness. To test whether the Krt8/18-coexpression is induced and is involved in cSCC invasion, we examined specimens from 21 pre-invasive and 24 invasive cSCC patients by immunohistochemistry, and the ectopic Krt8/18-coexpression was almost exclusively found in invasive cSCC. Further studies are needed to examine the clinical significance of ectopic Krt8/18-coexpression in cSCC. 相似文献
102.
Dentatorubral-pallidoluysian atrophy is caused by polyglutamine (polyQ) expansion in atrophin-1 (ATN1). Recent studies have shown that nuclear accumulation of ATN1 and cleaved fragments with expanded polyQ is the pathological process underlying neurodegeneration in dentatorubral-pallidoluysian atrophy. However, the mechanism underlying the proteolytic processing of ATN1 remains unclear. In the present study, we examined the proteolytic processing of ATN1 aiming to understand the mechanisms of ATN1 accumulation with polyQ expansion. Using COS-7 and Neuro2a cells that express the ATN1 gene, in which ATN1 was accumulated by increasing the number of polyQs, we identified a novel C-terminal fragment containing a polyQ tract. The mutant C-terminal fragment with expanded polyQ selectively accumulated in the cells, and this was also demonstrated in the brain tissues of patients with dentatorubral-pallidoluysian atrophy. Immunocytochemical and biochemical studies revealed that full-length ATN1 and C-terminal fragments displayed individual localization. The mutant C-terminal fragment was preferentially found in the cytoplasmic membrane/organelle and insoluble fractions. Accordingly, it is assumed that the proteolytic processing of ATN1 regulates the localization of C-terminal fragments. Accumulation of the C-terminal fragment was enhanced by inhibition of caspases in the cytoplasm of COS-7 cells. Collectively, these results suggest that the C-terminal fragment plays a principal role in the pathological accumulation of ATN1 in dentatorubral-pallidoluysian atrophy. 相似文献
103.
Kang SH Kim GR Seong M Baek SH Seol JH Bang OS Ovaa H Tatsumi K Komatsu M Tanaka K Chung CH 《The Journal of biological chemistry》2007,282(8):5256-5262
Ubiquitin-fold modifier 1 (Ufm1) is a recently identified new ubiquitin-like protein, whose tertiary structure displays a striking resemblance to ubiquitin. Similar to ubiquitin, it has a Gly residue conserved across species at the C-terminal region with extensions of various amino acid sequences that need to be processed in vivo prior to conjugation to target proteins. Here we report the isolation, cloning, and characterization of two novel mouse Ufm1-specific proteases, named UfSP1 and UfSP2. UfSP1 and UfSP2 are composed of 217 and 461 amino acids, respectively, and they have no sequence homology with previously known proteases. UfSP2 is present in most, if not all, of multicellular organisms including plant, nematode, fly, and mammal, whereas UfSP1 could not be found in plant and nematode upon data base search. UfSP1 and UfSP2 cleaved the C-terminal extension of Ufm1 but not that of ubiquitin or other ubiquitin-like proteins, such as SUMO-1 and ISG15. Both were also capable of releasing Ufm1 from Ufm1-conjugated cellular proteins. They were sensitive to inhibition by sulfhydryl-blocking agents, such as N-ethylmaleimide, and their active site Cys could be labeled with Ufm1-vinylmethylester. Moreover, replacement of the conserved Cys residue by Ser resulted in a complete loss of the UfSP1 and UfSP2 activities. These results indicate that UfSP1 and UfSP2 are novel thiol proteases that specifically process the C terminus of Ufm1. 相似文献
104.
Tsubaki M Kato C Manno M Ogaki M Satou T Itoh T Kusunoki T Tanimori Y Fujiwara K Matsuoka H Nishida S 《Molecular and cellular biochemistry》2007,304(1-2):53-60
Osteolytic lesions are rapidly progressive during the terminal stages of myeloma, and the bone pain or bone fracture that
occurs at these lesions decreases the patients’ quality of life to a notable degree. In relation to the etiology of this bone
destruction, it has been reported recently that MIP-1α, produced in large amounts in myeloma patients, acts indirectly on
osteoclastic precursor cells, and activates osteoclasts by way of bone-marrow stromal cells or osteoblasts, although the details
of this process remain obscure. In the present study, our group investigated the mechanism by which RANKL expression is induced
by MIP-1α and the effects of MIP-1α on the activation of osteoclasts. RANKL mRNA and RANKL protein expressions increased in
both ST2 cells and MC3T3–E1 cells in a MIP-1α concentration-dependent manner. RANKL mRNA expression began to increase at 1 h
after the addition of MIP-1α; the increase became remarkable at 2 h, and continuous expression was observed subsequently.
Both ST2 and MC3T3-E1 cells showed similar levels of increased RANKL protein expression at 1, 2, and 3 days after the addition
of MIP-1α. After the addition of MIP-1α, the amount of phosphorylated ERK1/2 and Akt protein expressions showed an increase,
as compared to the corresponding amount in the control group. On the other hand, the amount of phosphorylated p38MAPK protein
expression showed a decrease from the amount in the control group after the addition of MIP-1α. U0126 (a MEK1/2 inhibitor)
or LY294002 (a PI3K inhibitor) was added to ST2 and MC3T3-E1 cells, and was found to inhibit RANKL mRNA and RANKL protein
expression in these cells. When SB203580, a p38MAPK inhibitor, was added, RANKL mRNA and RANKL protein expression were increased
in these cells. MIP-1α was found to promote osteoclastic differentiation of C7 cells, an osteoclastic precursor cell line,
in a MIP-1α concentration-dependent manner. MIP-1α promoted differentiation into osteoclasts more extensively in C7 cells
incubated together with ST2 and MC3T3-E1 cells than in C7 cells incubated alone. These results suggested that MIP-1α directly
acts on the osteoclastic precursor cells and induces osteoclastic differentiation. This substance also indirectly induces
osteoclastic differentiation through the promotion of RANKL expression in bone-marrow stromal cells and osteoblasts. The findings
of this investigation suggested that activation of the MEK/ERK and the PI3K/Akt pathways and inhibition of p38MAPK pathway
were involved in RANKL expression induced by MIP-1α in bone-marrow stromal cells and osteoblasts. This finding may be useful
in the development of an osteoclastic inhibitor that targets intracellular signaling factors. 相似文献
105.
Crystal structure of Ufc1, the Ufm1-conjugating enzyme 总被引:2,自引:0,他引:2
Mizushima T Tatsumi K Ozaki Y Kawakami T Suzuki A Ogasahara K Komatsu M Kominami E Tanaka K Yamane T 《Biochemical and biophysical research communications》2007,362(4):1079-1084
Ubiquitin and ubiquitin-like protein-conjugating enzymes play central roles in posttranslational modification processes. The ubiquitin-fold modifier 1 (Ufm1), one of a variety of ubiquitin-like modifiers, is covalently attached to target proteins via Uba5 and Ufm1-conjugating enzyme 1 (Ufc1), which are analogous to the E1 and E2 ubiquitylation enzymes. As Ufm1-related proteins are conserved in metazoa and plants, the Ufm1 system likely plays important roles in various multicellular organisms. Herein, we report the X-ray structure of human Ufc1 determined at 1.6 A resolution. The Ufc1 structure comprises a canonical E2 domain and an additional N-terminal domain. The Uba5 binding site on Ufc1 was assigned by structural comparison of Ufc1 and Ubc12 and related mutational analyses. In addition, we show that the N-terminal unique domain of Ufc1 contributes to thermal stability. 相似文献
106.
Ose T Soler N Rasubala L Kuroki K Kohda D Fourmy D Yoshizawa S Maenaka K 《Structure (London, England : 1993)》2007,15(5):577-586
Selenocysteine (Sec) is the "21st" amino acid and is genetically encoded by an unusual incorporation system. The stop codon UGA becomes a Sec codon when the selenocysteine insertion sequence (SECIS) exists downstream of UGA. Sec incorporation requires a specific elongation factor, SelB, which recognizes tRNA(Sec) via use of an EF-Tu-like domain and the SECIS mRNA hairpin via use of a C-terminal domain (SelB-C). SelB functions in multiple translational steps: binding to SECIS mRNA and tRNA(Sec), delivery of tRNA(Sec) onto an A site, GTP hydrolysis, and release from tRNA and mRNA. However, this dynamic mechanism remains to be revealed. Here, we report a large domain rearrangement in the structure of SelB-C complexed with RNA. Surprisingly, the interdomain region forms new interactions with the phosphate backbone of a neighboring RNA, distinct from SECIS RNA binding. This SelB-RNA interaction is sequence independent, possibly reflecting SelB-tRNA/-rRNA recognitions. Based on these data, the dynamic SelB-ribosome-mRNA-tRNA interactions will be discussed. 相似文献
107.
Increasing evidence reveals the carcinogenicity of UVA radiation. We demonstrated that UVA-irradiated NADH induced damage to (32)P-labeled DNA fragments obtained from the p53 gene in the presence of Cu(II). Formamidopyrimidine glycosylase (Fpg)-sensitive lesions were formed at guanine residues, whereas piperidine-labile lesions occurred frequently at thymine residues. Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), upon UVA exposure in the presence of Cu(II), increased depending on NADH concentration. Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited the DNA damage, suggesting the involvement of reactive species derived from H(2)O(2) and Cu(I). UVA-irradiated riboflavin induced DNA cleavage through electron transfer at 5' guanine of the 5'-GG-3' sequence with both Fpg and piperidine treatments; Fpg induced less cleavage at the guanine residues than piperidine. These results imply that NADH may participate as an endogenous photosensitizer in UVA carcinogenesis via H(2)O(2) generation, producing metal-mediated mutagenic lesions such as 8-oxodG. 相似文献
108.
Kanie S Horibata K Kawano M Isogawa A Sakai A Matsuo N Nakanishi M Hasegawa K Yoshiyama K Maki H 《Genes & genetic systems》2007,82(2):99-108
To verify the extent of contribution of spontaneous DNA lesions to spontaneous mutagenesis, we have developed a new genetic system to examine simultaneously both forward mutations and recombination events occurring within about 600 base pairs of a transgenic rpsL target sequence located on Escherichia coli chromosome. In a wild-type strain, the recombination events were occurring at a frequency comparable to that of point mutations within the rpsL sequence. When the cells were UV-irradiated, the recombination events were induced much more sharply than point mutations. In a recA null mutant, no recombination event was observed. These data suggest that the blockage of DNA replication, probably caused by spontaneous DNA lesions, occurs often in normally growing E. coli cells and is mainly processed by cellular functions requiring the RecA protein. However, the recA mutant strain showed elevated frequencies of single-base frameshifts and large deletions, implying a novel mutator action of this strain. A similar mutator action of the recA mutant was also observed with a plasmid-based rpsL mutation assay. Therefore, if the recombinogenic problems in DNA replication are not properly processed by the RecA function, these would be a potential source for mutagenesis leading to single-base frameshift and large deletion in E. coli. Furthermore, the single-base frameshifts induced in the recA-deficient cells appeared to be efficiently suppressed by the mutS-dependent mismatch repair system. Thus, it seems likely that the single-base frameshifts are derived from slippage errors that are not directly caused by DNA lesions but made indirectly during some kind of error-prone DNA synthesis in the recA mutant cells. 相似文献
109.
Manabe T Tatsumi K Inoue M Makinodan M Yamauchi T Makinodan E Yokoyama S Sakumura R Wanaka A 《Cell death and differentiation》2007,14(6):1080-1085
L3/Lhx8 is a member of the LIM-homeobox gene family. Previously, we demonstrated that L3/Lhx8-null mice specifically lacked cholinergic neurons in the basal forebrain. In the present study, we conditionally suppressed L3/Lhx8 function during retinoic acid-induced neural differentiation of a murine embryonic stem (ES) cell line using an L3/Lhx8-targeted small interfering RNA (siRNA) produced by an H1.2 promoter-driven vector. Our culture conditions induced efficient differentiation of the ES cells into neurons and astrocytes, but far less efficient differentiation into oligodendrocytes. Suppression of L3/Lhx8 expression by siRNA led to a dramatic decrease in the number of cells positive for the cholinergic marker ChAT, and overexpression of L3/Lhx8 recovered this effect. However, no significant changes were observed in the number of Tuj1+ neurons and GABA+ cells. These results strongly suggest that L3/Lhx8 is a key factor in the cholinergic differentiation of murine ES cells and is involved in basal forebrain development. 相似文献
110.
A peculiar relationship between genetic diversity and adaptability in invasive exotic species: bluegill sunfish as a model species 总被引:1,自引:0,他引:1
A peculiar relationship exists between population genetics and invasion biology. Introduced populations often suffer a depletion
of genetic variation, but they can persist and adapt to new environments. Here, we show that this relationship is observed
in bluegill sunfish (Lepomis macrochirus), an invasive exotic fish in Japan. Genetic analysis using selectively neutral genetic markers reconfirmed that the bluegill
introduced into Japan from the United States in 1960 had a single origin with only 15 founders. The analysis also shows that
in the process of range expansion, the introduced bluegills experienced severe depletion of genetic diversity due to the founder
effect and/or genetic drift. Despite such a decline in genetic diversity, the bluegill populations exhibited a divergent feeding
morphology in response to the colonized environments. Such a morphological divergence can facilitate prey exploitation, thereby
causing a greater negative impact on native prey resources. Further, in a trophically polymorphic bluegill population in Lake
Biwa, physiological characteristics and genetic structures of the intestinal bacterial communities were associated with the
difference in diet among the trophic morphs in the host bluegill population. This empirical evidence suggests that despite
the severe decline in genetic diversity, the introduced bluegill populations rapidly adapted to the new environment and formed
diverse functional relationships with the native bacterial community. Thus, these findings suggest that genetic variation
at selectively neutral markers does not always predict adaptability and invasiveness in introduced populations. 相似文献