Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Galectin-7 is a beta-galactoside-binding animal lectin specifically expressed in stratified epithelia. Its expression is inducible by p53 and is down-regulated in squamous cell carcinomas. Other investigators previously showed that galectin-7 is a proapoptotic protein, and we showed that ectopic expression of galectin-7 in HeLa cells renders the cells more sensitive to a variety of apoptotic stimuli. In the present study, we showed that ectopic expression of galectin-7 in the human colon carcinoma cell line DLD-1 also made the cells more sensitive to apoptosis under various conditions. We also found that galectin-7-transfected DLD-1 (DLD-1-Gal7) cells grew significantly more slowly than control transfectants (DLD-1-V) under normal culture conditions in the absence of apoptosis. Moreover, a significantly lower number of colonies were formed from DLD-1-Gal7 cells than from DLD-1-V cells under anchorage-independent cell growth conditions. Most importantly, tumor formation from DLD-1-Gal7 cells was dramatically reduced compared with DLD-1-V cells when these cells were inoculated s.c. into severe combined immunodeficient mice. DLD-1-Gal7 tumors showed a significantly lower proliferation rate than DLD-1-V tumors as determined by in vivo 5-bromo-2'-deoxyuridine incorporation. DLD-1-Gal7 tumors also contained a lower density of blood vessels than DLD-1-V tumors, suggesting that ectopic expression of galectin-7 suppresses angiogenesis. This may partially account for the greater suppressive effect of galectin-7 on tumor growth in vivo than in vitro. Our results show that galectin-7 has a suppressive effect on tumor growth, suggesting that galectin-7 gene transfer or other means of specifically inducing galectin-7 expression may be a new approach for management of cancers.
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PMID:Suppression of tumor growth by galectin-7 gene transfer. 1531 6

Galectin 3 (Gal-3), a member of the beta-galactoside binding lectin family, exhibits antiapoptotic functions, and its aberrant expression is involved in various aspects of tumor progression. Here we show that p53-induced apoptosis is associated with transcriptional repression of Gal-3. Previously, it has been reported that phosphorylation of p53 at Ser46 is important for transcription of proapoptotic genes and induction of apoptosis and that homeodomain-interacting protein kinase 2 (HIPK2) is specifically involved in these functions. We show that HIPK2 cooperates with p53 in Gal-3 repression and that this cooperation requires HIPK2 kinase activity. Gene-specific RNA interference demonstrates that HIPK2 is essential for repression of Gal-3 upon induction of p53-dependent apoptosis. Furthermore, expression of a nonrepressible Gal-3 prevents HIPK2- and p53-induced apoptosis. These results reveal a new apoptotic pathway induced by HIPK2-activated p53 and requiring repression of the antiapoptotic factor Gal-3.
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PMID:Repression of the antiapoptotic molecule galectin-3 by homeodomain-interacting protein kinase 2-activated p53 is required for p53-induced apoptosis. 1673 36

The unicellular eukaryote Entamoeba histolytica is a human parasite that causes amebic dysentery and liver abscess. A genome-wide analysis of gene expression modulated by intestinal colonization and invasion identified an upregulated transcript that encoded a putative high-mobility-group box (HMGB) protein, EhHMGB1. We tested if EhHMGB1 encoded a functional HMGB protein and determined its role in control of parasite gene expression. Recombinant EhHMGB1 was able to bend DNA in vitro, a characteristic of HMGB proteins. Core conserved residues required for DNA bending activity in other HMGB proteins were demonstrated by mutational analysis to be essential for EhHMGB1 activity. EhHMGB1 was also able to enhance the binding of human p53 to its cognate DNA sequence in vitro, which is expected for an HMGB1 protein. Confocal microscopy, using antibodies against the recombinant protein, confirmed its nuclear localization. Overexpression of EhHMGB1 in HM1:IMSS trophozoites led to modulation of 33 transcripts involved in a variety of cellular functions. Of these, 20 were also modulated at either day 1 or day 29 in the mouse model of intestinal amebiasis. Notably, four transcripts with known roles in virulence, including two encoding Gal/GalNAc lectin light chains, were modulated in response to EhHMGB1 overexpression. We concluded that EhHMGB1 was a bona fide HMGB protein with the capacity to recapitulate part of the modulation of parasite gene expression seen during adaptation to the host intestine.
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PMID:Characterization of an Entamoeba histolytica high-mobility-group box protein induced during intestinal infection. 1865 54

The role of abrin, a toxic lectin isolated from seeds of Abrus precatorius Linn in inducing apoptosis in murine Dalton's Lymphoma Ascites (DLA) cells was evaluated. Abrin when incubated at the concentration of 10 ng per million DLA cells could bring about cell death as typical morphological changes with apoptosis. However, necrotic cell death dominated when a higher dose of abrin was used. DNA samples, isolated from DLA cells treated with abrin showed fragmentation. Abrin brought about induction of apoptosis by stimulating the expression of pro-apoptotic Caspase-3, at the same time blocking the expression of Bcl-2, which is an anti apoptotic gene. However, the expression of tumor suppressor gene p53 has not been observed in control and abrin-treated DLA cells. Results suggested that abrin effectively induced apoptotic changes in the tumor cells that led to cellular death.
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PMID:Regulation of Caspase-3 and Bcl-2 Expression in Dalton's Lymphoma Ascites Cells by Abrin. 1895 74

Polygonatum cyrtonema lectin (PCL), a mannose-binding lectin, has been reported to induce cytotoxicity and apoptosis. Herein, we demonstrated that PCL-induced apoptosis and autophagy in A375 cells. The apoptotic mechanism was that PCL treatment regulated Bax, Bcl-xL and Bcl-2 proteins, leading to mitochondrial depolarization, cytochrome c release and caspase activation. Subsequently, we found that PCL treatment abrogated glutathione antioxidant system and induced mitochondria to generate ROS accumulation, resulting in p38-p53 activation. Moreover, we confirmed that the ROS-p38-p53 pathway was involved in PCL-induced autophagy. In conclusion, these results indicate that PCL induces apoptosis and autophagy via a mitochondrial-mediated ROS-p38-p53 pathway.
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PMID:Polygonatum cyrtonema lectin induces apoptosis and autophagy in human melanoma A375 cells through a mitochondria-mediated ROS-p38-p53 pathway. 1901 May 91

The human lectin galectin-7 (Gal-7; p53-induced gene-1) has anti- and pro-malignant features in different in vitro models. We tried to clarify relation of its expression to cellular and clinical parameters in head and neck squamous and basal cell carcinomas. Using a non-cross-reactive antibody, immunohistochemical staining in squamous cell epithelia (epidermis, epithelium of oropharynx and larynx) (n = 57), squamous cell carcinomas (n = 47) and lymph node metastases (n = 25), as well as basal cell carcinomas (n = 10) were studied. This monitoring was flanked by processing to assess the level of differentiation (cytokeratins 10 and 14), proliferation (Ki67) and basal lamina formation (collagen IV). The results were correlated with clinical and pathological findings (grading, TNM-staging, extracapsular spread, angio- and lymphangioinvasion, perineural invasion, recurrence and survival). Gal-7 resides in all layers of epithelia with cytoplasmic and nuclear localization in normal specimens. Basal cell carcinomas were devoid of the Gal-7 respective signal. Squamous cell carcinomas were positive, presenting different staining profiles. Intense staining was predominantly found in squamous cell cancers with high degrees of differentiation and keratinization. Fittingly, poor level of differentiation (P = 0.0009), absence of keratinization (P = 0.0105) and significant discontinuity or absence of collagen IV expression in the peritumoral basal lamina (P = 0.0024) was found in Gal-7-negative tumors. Gal-7 presence was not related to gender, primary tumor site, T-stage, N-stage, clinical stage, extracapsular spread, angio- and lymphangioinvasion, perineural spread or treatment outcome at a statistically significant level. Immunohistochemical analysis revealed a positive correlation for differentiation and keratinization to Gal-7 presence in squamous cell carcinomas. Absence of Gal-7 expression was detected in basal cell carcinomas. These clinical data delineate Gal-7 influence on differentiation in vivo, without evidence for a role in dissemination reported for lymphoma.
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PMID:Galectin-7: will the lectin's activity establish clinical correlations in head and neck squamous cell and basal cell carcinomas? 1901 43

Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid-binding lectin, has been reported to display remarkable inhibitory and cytotoxic activity toward cancer cells. However, the precise mechanism by which PCL induces tumor cell death is still only rudimentarily understood. In the present study, PCL was shown to markedly inhibit the growth of human melanoma A375 cells with concomitant low toxicity to the normal melanocytes. Subsequently, PCL was found to simultaneously induce A375 cell apoptosis and autophagy. The mechanism of apoptosis following treatment with PCL involved regulation of Bax, Bcl-x(L) and Bcl-2 proteins, which then caused collapse of the mitochondrial membrane potential, leading to cytochrome c release and caspase activation. The treatment with PCL also abrogated the glutathione antioxidant system, and induced mitochondria to generate massive ROS accumulation, which subsequently resulted in p38 and p53 activation. Further experimental data confirmed that the ROS-p38-p53 pathway could be involved in the stimulation of autophagy, suggesting that autophagy may play a death-promoting role via the above-mentioned apoptotic pathway. In conclusion, these findings indicate that PCL induces both apoptosis and autophagy in cancer cells through a mitochondria-mediated ROS-p38-p53 pathway.
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PMID:Molecular mechanisms of Polygonatum cyrtonema lectin-induced apoptosis and autophagy in cancer cells. 1913 34

Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for beta-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC(50)s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl(T315I), or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines. Collectively, hGal9 is a candidate agent that may overcome various kinds of resistance to treatment for CML and may suggest that ATF3 may be a new target molecule for the development of new treatment modalities that can overcome resistance to currently available chemotherapeutics.
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PMID:Targeting activating transcription factor 3 by Galectin-9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia. 2057 Oct 63

Cutaneous angiosarcoma is a very rare but aggressive tumor. Angiosarcoma of the scalp is very rare, and a review of the world literature revealed less than 60 cases. Here, the author reports a case of poorly differentiated angiosarcoma of the scalp. The pathological diagnosis was very difficult. A 70-year-old Japanase man was admitted to our hospital complaining of red mass of the scalp. An excisional biopsy was done. The biopsy showed proliferation of malignant spindle cells in the dermis. Apparent differentiation was not recognized. Invasion into the lateral dermis and subcutis was recognized. There were many mitotic figures and a few foci of necrosis. The size was 2 x 2 x 3 cm. Intracytoplasmic vacuoles were recognized in the malignant tumor cells in some places. A few vague vasoformative features were recognized in one very small area. Immunohistochemically, the malignant spindle cells were positive for factor VIII-related antigen (F-VIII-RA), Ulex lectin, CD31, CD34, vimentin, p53 protein. The Ki-67 labeling was 76%. In contrast, the tumor cells were negative for cytokeratins, epithelial membrane antigen, desmin, S100 protein, alpha-smooth muscle antigen, bcl-2, melanosome, and myoglobin. The intracytoplasmic vacuoles were strongly positive for F-VIII-RA, Ulex lectin, CD31, and CD34, The abortive vasoformative channels were moderately positive for these endothelial markers. A pathologic diagnosis of angiosarcoma of the scalp was made. Chemoradiation and immunotherapy were performed. However, the tumor recurred several times, and ultimately metastasized to the systemic bones and lungs. The patient died of systemic carcinomatosis 33 months after the first manifestation.
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PMID:Fatal poorly differentiated angiosarcoma of the scalp. 2060 36

Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid-binding plant lectin, has recently drawn a rising attention for cancer biologists because PCL bears remarkable anti-tumor activities and thus inducing programmed cell death (PCD) including apoptosis and autophagy in cancer cells. In this review, we focus on exploring the precise molecular mechanisms by which PCL induces cancer cell apoptotic death such as the caspase-dependent pathway, mitochondria-mediated ROS-p38-p53 pathway, Ras-Raf and PI3K-Akt pathways. In addition, we further elucidate that PCL induces cancer cell autophagic death via activating mitochondrial ROS-p38-p53 pathway, as well as via blocking Ras-Raf and PI3K-Akt pathways, suggesting an intricate relationship between autophagic and apoptotic death in PCL-induced cancer cells. In conclusion, these findings may provide a new perspective of Polygonatum cyrtonema lectin (PCL) as a potential anti-tumor drug targeting PCD pathways for future cancer therapeutics.
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PMID:Polygonatum cyrtonema lectin, a potential antineoplastic drug targeting programmed cell death pathways. 2132 60


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