Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50502 (Hip)
 7,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Her-2/neu (ErbB2) is a transmembrane tyrosine kinase and acts as a co-receptor for the other EGFR family members. It is well known that high expression of Her-2/neu is associated with a poor prognosis in breast cancer. Quercetin, a flavonoid present in many vegetables and fruits, has been studied extensively as a chemoprevention agent in several cancer models. In this study, we observed that quercetin decreased the level of Her-2/neu protein in time- and dose-dependent manners and also inhibited the downstream survival PI3K-Akt signaling pathway in Her-2/neu-overexpressing breast cancer SK-Br3 cells. We also observed that quercetin induced polyubiquitination of Her-2/neu. When the proteasome pathway was blocked by MG-132 during quercetin treatment, accumulation of the NP-40 insoluble form of Her-2/neu occurred. Interestingly, data from immunocomplex studies revealed that quercetin promoted interaction between Her-2/neu and Hsp90 which is a molecular chaperone involved in stabilization of Her-2/neu. In this condition, inhibition of Hsp90 activity by a specific inhibitor, geldanamycin (GA), or intracellular ATP depletion caused dissociation of Hsp90 from Her-2/neu and promoted ubiquitination and down-regulation of Her-2/neu protein. In addition, the carboxyl terminus of Hsc70-interacting protein (CHIP), a chaperone-dependent E3 ubiquitin ligase, played a crucial role in the quercetin-induced ubiquitination of Her-2/neu. Inhibition of tyrosine kinase activity of Her-2/neu by quercetin could indicate an lateration in the Her-2/neu structure which promotes CHIP recruitments and down-regulation of Her-2/neu. We believe that by using quercetin, new therapeutic strategies can be developed to treat Her-2/neu overexpressing cancers.
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PMID:Quercetin-induced ubiquitination and down-regulation of Her-2/neu. 1865 87

Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gas1 (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner. Surprisingly, pull-down experiments suggest that a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO. Here we report biochemical, biophysical and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.
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PMID:The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. 1879 98

Knee rotationplasty was initially proposed for the reconstruction of the knee joint in the congenital hypoplasia of the femur. Its application was extended to functional reconstruction of the knee joint after wide resection of malignant bone or soft tissue tumor around the knee. It has also been shown to salvage a failed knee-sparing surgery due to infection or the aseptic loosening of the prosthesis. Hip rotationplasty has been described as a method for the reconstuction of hip function, as well as in the knee joint, in the case of a primary malignant tumor of the proximal part of the femur in children. It has also been described as having a surgical application for the severe congenital deficiency of the proximal part of the femur to reconstruct hip and knee joints, as well as for the massive bone defect of the proximal part of the femur due to infection to mimic a functional femoral shaft. This article reports a case where the hip joint was secondarily reconstructed with hip rotationplasty after subtotal resection of the femur due to infection of the hip hemiarthroplastic prosthesis and osteomyelitis of the hip joint and femur.
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PMID:Hip rotationplasty with antibiotic-loaded bone cement spacer for severe infection following limb-sparing surgery. 1929 68

Whole cereal grain foods are rich in phytate, a Ca chelator, and could increase the risk of hip fracture. The objective of the present study was to investigate the association between baseline whole grain intake and incident hip fracture. In the present study, 29 192 women who at baseline in 1986 were aged 55-69 years, free of diabetes, and reported a plausible energy intake of 2508-20 900 kJ/d and reported no fracture since the age of 35 years were followed. Hip fracture (n 746) was self-reported in five questionnaires through 2004. Of 1451 hip fractures identified passively by Medicare linkage through 31 December 2004 (Medicare hip fracture), 507 had also been self-reported. Whole grain intake was inversely related to Medicare hip fracture (P trend = 0.02), but it was unrelated to self-reported hip fracture (P trend = 0.27). The hazard ratio in the highest to lowest quintile of whole grain intake for incident Medicare-only hip fracture (n 944) was 0.66 (95% CI 0.53, 0.82) after adjustment for age, energy intake, education, BMI, waist-to-hip ratio, farm residence, physical activity, oestrogen use, smoking, alcohol use, history of cancer and other dietary variables. Medicare-only cases may have failed to self-report due to severe illness; hazard ratio for total mortality after hip fracture was 2.92 (2.37, 3.59) for Medicare-only cases v. Medicare-confirmed self-reported cases. In conclusion, in this cohort, the inverse association between whole grain intake and hip fracture was explained by ascertainment bias. Whole grain intake may increase the ability to respond to a questionnaire and self-report hip fracture, and could reflect less undocumented frailty.
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PMID:Whole grain intake, incident hip fracture and presumed frailty in the Iowa Women's Health Study. 2056 26

We investigated the excess mortality risk associated with fractures of the hip. Data related to 29 134 patients who underwent surgery following a fracture of the hip were obtained from the Scottish Hip Fracture Audit database. Fractures due to primary or metastatic malignancy were excluded. An independent database (General Register Office (Scotland)) was used to validate dates of death. The observed deaths per 100 000 of the population were then calculated for each group (gender, age and fracture type) at various time intervals up to eight years. A second database (Interim Life Tables for Scotland, Scottish Government) was then used to create standardised mortality ratios. Analysis showed that mortality in patients aged > 85 years with a fracture of the hip tended to return to the level of the background population between two and five years after the fracture. In those patients aged < 85 years excess mortality associated with hip fracture persisted beyond eight years. Extracapsular hip fractures and male gender also conferred increased risk.
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PMID:Change in long-term mortality associated with fractures of the hip: evidence from the scottish hip fracture audit. 2059 20

The molecular chaperone heat shock protein 90 (Hsp90) and the co-chaperone/ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP) control the turnover of client proteins. How this system decides to stabilize or degrade the client proteins under particular physiological or pathological conditions is unclear. We report here a novel client protein, the SUMO2/3 protease SENP3, that is sophisticatedly regulated by CHIP and Hsp90. SENP3 is maintained at a low basal level under non-stress condition due to Hsp90-independent CHIP-mediated ubiquitination. Upon mild oxidative stress, SENP3 undergoes thiol modification, which recruits Hsp90. Hsp90/SENP3 association protects SENP3 from CHIP-mediated ubiquitination and subsequent degradation, but this effect of Hsp90 requires the presence of CHIP. Our data demonstrate for the first time that CHIP and Hsp90 interplay with a client alternately under non-stress and stress conditions, and the choice between stabilization and degradation is made by the redox state of the client. In addition, enhanced SENP3/Hsp90 association is found in cancer. These findings provide new mechanistic insight into how cells regulate the SUMO protease in response to oxidative stress.
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PMID:Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90. 2092 58

The maintenance of eukaryotic telomeres requires telomerase, which is minimally composed of a telomerase reverse transcriptase (TERT) and an associated RNA component. Telomerase activity is tightly regulated by expression of human (h) TERT at both the transcriptional and post-translational levels. The Hsp90 and p23 molecular chaperones have been shown to associate with hTERT for the assembly of active telomerase. Here, we show that CHIP (C terminus of Hsc70-interacting protein) physically associates with hTERT in the cytoplasm and regulates the cellular abundance of hTERT through a ubiquitin-mediated degradation. Overexpression of CHIP prevents nuclear translocation of hTERT and promotes hTERT degradation in the cytoplasm, thereby inhibiting telomerase activity. In contrast, knockdown of endogenous CHIP results in the stabilization of cytoplasmic hTERT. However, it does not affect the level of nuclear hTERT and has no effect on telomerase activity and telomere length. We further show that the binding of CHIP and Hsp70 to hTERT inhibits nuclear translocation of hTERT by dissociating p23. However, Hsp90 binding to hTERT was not affected by CHIP overexpression. These results suggest that CHIP can remodel the hTERT-chaperone complexes. Finally, the amount of hTERT associated with CHIP peaks in G(2)/M phases but decreases during S phase, suggesting a cell cycle-dependent regulation of hTERT. Our data suggest that CHIP represents a new pathway for modulating telomerase activity in cancer.
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PMID:CHIP promotes human telomerase reverse transcriptase degradation and negatively regulates telomerase activity. 2095 53

LKB1 is a tumor suppressor that is constitutionally mutated in a cancer-prone condition, called Peutz-Jeghers syndrome, as well as somatically inactivated in a sizeable fraction of lung and cervical neoplasms. The LKB1 gene encodes a serine/threonine kinase that associates with the pseudokinase STRAD (STE-20-related pseudokinase) and the scaffolding protein MO25, the formation of this heterotrimeric complex promotes allosteric activation of LKB1. We have previously reported that the molecular chaperone heat shock protein 90 (Hsp90) binds to and stabilizes LKB1. Combining pharmacological studies and RNA interference approaches, we now provide evidence that the co-chaperone Cdc37 participates to the regulation of LKB1 stability. It is known that the Hsp90-Cdc37 complex recognizes a surface within the N-terminal catalytic lobe of client protein kinases. In agreement with this finding, we found that the chaperones Hsp90 and Cdc37 interact with an LKB1 isoform that differs in the C-terminal region, but not with a novel LKB1 variant that lacks a portion of the kinase N-terminal lobe domain. Reconstitution of the two complexes LKB1-STRAD and LKB1-Hsp90-Cdc37 with recombinant proteins revealed that the former is catalytically active whereas the latter is inactive. Furthermore, consistent with a documented repressor function of Hsp90, LKB1 kinase activity was transiently stimulated upon dissociation of Hsp90. Finally, disruption of the LKB1-Hsp90 complex favors the recruitment of both Hsp/Hsc70 and the U-box dependent E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein) that triggers LKB1 degradation. Taken together, our results establish that the Hsp90-Cdc37 complex controls both the stability and activity of the LKB1 kinase. This study further shows that two chaperone complexes with antagonizing activities, Hsp90-Cdc37 and Hsp/Hsc70-CHIP, finely control the cellular level of LKB1 protein.
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PMID:Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1. 2289 68

The aim of this study was to evaluate the postoperative morbidity at the donor site and the long-term outcome after the harvest of bicortical iliac bone grafts, including the iliac crest and the anterior superior iliac spine (ASIS), by using a confirmed score. We retrospectively examined 54 consecutive patients who had had vascularised iliac bone grafts harvested to reconstruct different parts of the mandible. We used the Harris Hip Score to evaluate objectively the long-term postoperative morbidity at the donor site. Of 54 patients, 20 were female (37%) and 34 male (63%), with a mean age of 49 years (range 12-81). The causes of the bony defects were malignancy (n=37, 69%), benign tumours (n=7, 13%), osteomyelitis (n=9, 17%), and atrophy of the alveolar ridge (n=1, 2%). All transplants healed adequately. A total of 38/52 patients (73%) had a score of more than 80 points, which defines clinical success. Vascularised iliac bone grafts offer excellent bony dimensions with optimal shape to be used for reconstruction of different parts of the mandible. They can be harvested bicortically, including the iliac crest and the ASIS, with acceptable morbidity at the donor site. The Harris Hip Score is an appropriate tool for the evaluation of long-term impairment at the donor site after the harvest of vascularised iliac bone grafts, and it could be used to compare the results of different studies.
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PMID:Functional long-term results after the harvest of vascularised iliac bone grafts bicortically with the anterior superior iliac spine included. 2267 14

There are very few cases of radiation-induced femoral head necrosis described in the literature, therefore, this case will add new knowledge and highlights important aspects in the diagnosis and management of this uncommon condition. Our patient was 74 years old and presented with left hip and groin pain for 8 months, with no previous history of trauma or osteoarthritis. However, he had been treated for metastatic prostate cancer, to the pelvis and roof of the left acetabulum, with androgen ablation, and radiotherapy 5 years before presentation. Examination of the left hip revealed painful movements, but no restriction in the range of motion. Initial X-rays did not show any abnormalities, but MRI scan revealed a suspicious lesion in the roof of the left acetabulum, with no indication of secondary weakening of the femoral neck. The patient was therefore referred to the oncologists to consider radiotherapy, but they were not convinced it was metastatic, because he had no new urinary symptoms, and the PSA remained normal throughout this period. He was subsequently referred for a bone scan to look for possible secondary lesions (from the prostate gland), but this did not reveal any abnormal increased uptake. Three months later, he was reviewed in the clinic with a repeat X-ray of the pelvis which revealed complete destruction of the left femoral head and the acetabular roof, but CT-guided biopsy revealed no evidence of malignancy in the left hip. However, in view of the persistent pain and radiological evidence of left hip destruction, the patient had left Total Hip Replacement (THR), and excellent post-operative recovery. He mobilised fully, and was discharged on day five. Histology of the femoral head and hip capsule, revealed no evidence of metastasis from the prostate cancer, but confirmed osteonecrosis of the femoral head, presumably caused by the previous radiotherapy. MRI of the spine was clear and he was discharged to the oncologists and urologists for follow up.
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PMID:Radiation-induced femoral head necrosis. 2337 87


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