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| 1 | 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 |
| 2 | Molecular profile of oligoden - drogliomas in young patients 显示文摘 | Suri V Jha P Agm'wal S | 2011 | Neuro Oncol2011，13，10： | 1 |
| 3 | The limits of economy of material in frame structure显示文摘 | Michell AGM | 1904 | Philosphical Magazine1904，6，8： | 1 |
| 4 | Preval ncia de altera es do ndice tornozelo-bra 0 em indiv duos portadores assintom ticos de doen a arterial obstrutiva perif rica显示文摘 | Torres AGM Machado EG Lopes' TS | 2012 | Rev Bras Cardiol2012，25，2： | 1 |
| 5 | Airmed-cardio:a GSM and Internet services-based system for out-of-hospital follow-up of cardiac patients显示文摘 | Carlos HS Mario PC Miguel AGM | 2005 | IEEE Transactions on Information Technology in Biomedicine2005，9，1： | 1 |
| 6 | Energy generation in parasitic helminthes显示文摘 | Tielens AGM | 1994 | Parasitology Today1994，10，： | 1 |
| 7 | Dietary native resistant starch but not retrograded resistant starch raises magnesium and calcium in rats显示文摘 | SCHULZ AGM VAN AMELSVOORT JMM BEYNEN AC | 1993 | American Institute of Nutrition1993，，4： | 1 |
| 8 | Energy generation in parasitic helminths显示文摘 | | 1994 | Parasitol Today1994，10，： | 1 |
| 9 | Dess-Martin periodinane oxidation of alcohols in the presence of stabilized phosphorus ylides: a convenient method for the homologation of alcohols via unstable aldehydes 显示文摘 | Barrett AGM Hamprecht D Ohkubo M | 1997 | J Org Chem1997，62，26： | 1 |
| 10 | Effects of concepts of career plateaus on performance, work satisfaction and commitment 显示文摘 | Nachbagauer AGM Riedl G | 2002 | International Journal of Manpower2002，23，8： | 1 |
| 11 | Genetic control of dihydroflavonol 4-reductase gene expression in Petunia hybrida 显示文摘 | HUITS HSM GERATS AGM KREIKE M | 1994 | Plant J1994，6，3： | 1 |
| 12 | Contribution of starter cultures to the proteolytic process of a fermented non-dried whole muscle ham product 显示文摘 | Scannella AGM Kenneallyb PM Arendtb EK | 2004 | International Journal of Food Microbiology2004，，93： | 1 |
| 13 | Extension of life-span by introduction of tdomerase into normal human cells显示文摘 | Bodnar AGM Ouellettee M Frolkis M | 1998 | Science1998，279，： | 1 |
| 14 | Effects of culture media on detection of methicillin resistance in Staphylococcus aureus and coagulase negative staphylococci by disc diffusion methods显示文摘 | Milne LM Crow MR Emptage AGM Selkon JB | | 0，，： | 1 |
| 15 | A recombinant glycoprotein vaccine for herpes simplex type 2 :Safety and efficacy显示文摘 | Langenburg AGM Burke RL Adair SF | 1995 | Ann Intern Med1995，122，： | 1 |
| 16 | Glutathione transferase as a marker for tubular damage after trichloroethylene expoxure显示文摘 | Burning T Sundberg AGM Birner G | 1999 | Arch Toxicol1999，73，45： | 1 |
| 17 | Energy generation in parasitic helminths 显示文摘 | Tielens AGM | 1994 | Parasitol Today1994，10，： | 1 |
| 18 | Clinical relevance of oxidative stress in male factor infertility:an update 显示文摘 | Agm'wal A Makker K Sharma R | 2008 | Am J Reprod Immunol2008，59，1： | 1 |
| 19 | Energy generation in parasitic helminthes显示文摘 | Tielens AGM | 1994 | Parasitology Today1994，10，： | 1 |
| 20 | Ocular dermoids: 116 consecutive cases 显示文摘 | del Roeio AGM Navas A Haber A | 2013 | Eye & Contact Lens2013，39，2： | 1 |
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