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| 1 | The MDM2-p53 pathway revisited显示文摘The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy. | Subhasree Nag Jiangjiang Qin Kalkunte S.Srivenugopal Minghai Wang Ruiwen Zhang | 2013 | The Journal of Biomedical Research2013，27，4： | 13 |
| 2 | New insights into estrogenic regulation of O^6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O^6-benzylguanine indicates fresh avenues for therapy显示文摘Endocrine therapy using estrogen receptor-α(ER-α) antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers.To exploit any DNA repair deficiencies associated with endocrine therapy,we investigated the functional and physical interactions of ER-α with O^6-methylguanine DNA methyltransferase(MGMT),a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents.The ER-α-positive breast cancer cell lines(MCF-7,T47D) and ER- negative cell lines(MDAMB-468,MDAMB-231),and established inhibitors of ER-α and MGMT,namely,ICI-182,780(Faslodex) and O^6-benzylguanine,respectively,were used to study MGMT- ER interactions.The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements(EREs) and two antioxidant-responsive elements(AREs).MGMT expression was upregulated by estrogen,downregulated by tamoxifen in Western blot and promoter-linked reporter assays.Similarly,both transient and stable transfections of Nrf-2(nuclear factor-erythroid 2-related factor-2)increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this drugresistance determinant.Of the different ER-α antagonists tested,the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose,time and ER-α dependent manner,similar to O^6-benzylguanine.Interestingly,fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O^6-benzylguanine also induced a specific loss of ER-α and MGMT proteins in MCF-7 and T47 D breast cancer cells with similar kinetics.Immunoprecipitation revealed a specific association of ER-α and MGMT proteins in breast cancer cells.Furthermore,silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-α proteins.The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated.Fulvestrant enhanced the cytotoxicity of MGMT-targeted alkylating agents,namely,temozolomide and BCNU by 3 to 4-fold in ER-α positive cells,but not in ER-negative cells.We conclude that MGMT and ER-α proteins exist as a complex and are co-targeted for ubiquitin-conjugation and subsequent proteasomal degradation.The findings offer a clear rationale for combining alkylating agents with endocrine therapy. | Ameya Paranjpe Nathan I. Bailes Santhi Konduri George C. Bobustuc Francis Ali-Osman Mohd. A. Yusuf Surendra R. Punganuru Hanumantha Rao Madal Debasish Basak AGM Mostofa Kalkunte S. Srivenugopa | 2016 | The Journal of Biomedical Research2016，30，5： | 5 |
| 3 | Enhanced chemosensitivity of p73α gene transferred into H1299 cell line of human lung adenocarcinoma显示文摘Objective: To study the effects of transferred wild type p73α gene on the sensitivity to the chemotherapeutic agents and the growth of p53-null H1299 cells of human lung adenocarcinoma. Methods: The pcDNA3-HA-p73α plasmid was transferred into the cultured p53-null H1299 cells of human lung adenocarcinoma with the mediation of Dosper liposome; The cells resistant to G418 were selected. The expression of p73α gene in the cells was examined with Western blot. MTT assay was used to analyze the response of the transfected cells to cis-dichlorodiamine platinum (cDDP) and adriamycin (ADM). The rate of drug-induced apoptosis of the transfected cells was determined with flow cytometry and DNA fragmentation assay. The changes of the biological behaviors were observed with colony formation assay. Results: The transfected H1299 cells of human lung adenocarcinoma over-expressed p73α protein stably. MTT assay showed that the IC 50 values of cDDP and ADM were reduced by approximately 7 fold and 130 fold respectively in the transfected cells as compared with the untransfected ones. Lower concentration of the chemotherapeutic agents (1.25 μmol/L of cDDP and 0.05 μmol/L of ADM) could be employed to suppress markedly the growth of the transfected H1299 cells. The apoptotic rate induced by cDDP was increased from 10.1% to 38 4% (P<0.01) and that of ADM from 12.1% to 49.3% (P<0.01). The clonogenecity after the administration of chemotherapeutic agents was significantly lower in the transfected H1299 cells than in the parental cells (P<0.01). The sensitive enhancement ratios were 1.8 and 2.6 for cDDP and ADM respectively. Conclusion: The transfection of H1299 cells with wild type p73α gene results in an increase of the sensitivity of the cells to chemotherapeutic agents. | 何勇 范士志 Kalkunte S Srivenugopal 蒋耀光 秦川 | 2004 | Journal of Medical Colleges of PLA(China)2004，19，3： | 2 |
| 4 | Therapeutic angiogenesis in Buerger’s disease (thromboangiitis obliterans) patients with critical limb ischemia by autologous transplantation of bone marrow mononuclear cells显示文摘 | Vishnu Motukuru Kalkunte R. Suresh Vivekanand Vivekanand Sumanth Raj K.R. Girija | 2008 | Journal of Vascular Surgery2008，，6： | 2 |
| 5 | Multiple pregnancy failures:an immunological paradigm显示文摘 | Matthiesen L Kalkunte S Sharma S | 2012 | American Journal of Reproductive Immunology2012，67，： | 1 |
| 6 | The water channel aquaporin 1 is a novel molecular target of polychlorinated biphenyls for in utero anomalies 显示文摘 | Tewari N Kalkunte S Murray DW | 2009 | J Biol Chem2009，284，15： | 1 |
| 7 | Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf 显示文摘 | Kalkunte S Brard L Granai C O | 2005 | Angiogenesis2005，8，： | 1 |
| 8 | Vascular endothelial growth factor C facilitates immune tolerance and endo- vascular activity of human uterine NK ceils at the maternal - fetal interface显示文摘 | KALKUNTE S S MSELLE T F NORRIS W E | 2009 | J Immunol2009，182，7： | 1 |
| 9 | Uterine Regulatory T eells,IL-10 and hypertension显示文摘 | Nevers T Kalkunte S Sharma S | 2011 | Am J Reprod Immunol2011，66，1： | 1 |
| 10 | The water channel aquaporin 1 is a novel molecular target of polychlorinated biphenyls for in utero anomalies显示文摘 | Tewari N Kalkunte S Murray D W | 2009 | J Biol Chem2009，284，15： | 1 |
| 11 | Degradation of NF-KB, p53 and other regulatory redox- sensitive proteins by thiolconjugating and nitrosylating drugs in human tumor cells 显示文摘 | AMEYA PARANJPE KALKUNTE S SRIVENUGOPAL | 2013 | Carcinogenesis2013，34，5： | 1 |
| 12 | The water channel aqua- porin 1 is a novel molecular target of polyehlorinated biphenyls forin utero anomalies显示文摘 | Tewari N Kalkunte S Murray DW | 2009 | J Biol Chem2009，284，15： | 1 |
| 13 | Inhibition of angiogenesis by vitamin D-binding protein:characterization of anti-endothelial activity of DBP-maf显示文摘 | Kalkunte S Brard L Granai CO | | 0，，04： | 1 |
| 14 | In vitro and in vivo evidence for lack of endovascular remodeling by third trimester trophoblasts显示文摘 | Kalkunte S Lai Z Tewari N | 2008 | Placenta2008，29，10： | 1 |
| 15 | Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Pro- vide a Basis for an in Vitro Predictive Assay显示文摘 | Kalkunte S Boij R Norris W | 2010 | Am J Pathol2010，177，5： | 1 |
| 16 | Evolution of non - cyto-toxic uterine natural killer cells显示文摘 | Kalkunte S Chichester CO Gotsch F | 2008 | Am J Reprod Immunol2008，59，5： | 1 |
| 17 | Vascular IL-10:A protective role in preeclampsia显示文摘 | Kalkunte S Nevers T Norris WE | 2011 | J Reprod Immunol2011，88，2： | 1 |
| 18 | Vascular IL-10: a protec- tive role in preeclampsia 显示文摘 | Kalkunte S Nevers T Norris W E | 2011 | J Reprod Immunol2011，88，2： | 1 |
| 19 | Evolution of non-cytotoxic uterine natural killer cells显示文摘 | Kalkunte S Chichester CO Gotsch F | 2008 | Am J Reprod Immunol2008，59，5： | 1 |
| 20 | A critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice 显示文摘 | Lai Z B Kalkunte S Sharma S | 2011 | Hypertension2011，57，： | 1 |
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