Photo of Bertal H Aktas,  PhD

Bertal H Aktas, PhD

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 525-3142

Bertal H Aktas, PhD

Brigham And Women's Hospital


  • Assistant Professor, Medicine, Harvard Medical School
  • Associate Molecular Biologist, Medicine, Brigham And Women's Hospital


Research Abstract

As a researcher, my major commitment is to investigate cellular proliferation and transformation, and molecular and chemical genetics of the integrated endoplasmic reticulum stress response (IERSR).

Cellular proliferation and transformation. Origins of this research lay in my discovery that Cyclin D1 and p27Kip1 link Ras signaling to cell cycle machinery. Ras, activated in 15-20% of human cancers, interacts with translation initiation factors in a feed-forward loop to increase expression of oncogenic proteins at the level of translation. The realization that translation initiation is at the apex of many oncogenic pathways prompted me to test the hypothesis that translation initiation factors can be targeted for cancer therapy.

My collaborators and I have identified several small molecule translation initiation inhibitors using high throughput assays. These include diaryl-oxindoles, thiozolidones, and N,N’-diarylureas that inhibit eIF2.GTP.met-tRNAi ternary and thiozolidonehydrozone-based agents that inhibit eIF4F translation initiation complex. I also developed assays to accredit the in vivo mechanism of action and the specificity of these agents. In the course of these studies I identified heme regulated inhibitor kinase as a novel target for cancer therapy. These studies are currently supported by an RO1 and an industry grant on which I am the Principal Investigator.

Molecular and chemical genetics of the IERSR. The IERSR maintains a balance between demand and capacity for folding newly synthesized proteins. Defects of the IERSR are associated with multiple human disorders, including cancer, and neuro-degeneration. That the eIF2.GTP.met-tRNAi is a critical component of the IERSR prompted me to study the molecular and chemical genetics of the IERSR. My group utilized high throughput assays to screen whole-genome human siRNA and small molecule libraries and identified unique genetic and chemical modifiers of the IERSR. I will capitalize on these probes to study biology of endoplasmic reticulum and delineate the role of IERSR in the pathobiology of human disorders, particularly cancer. In collaboration with leading experts, I will attempt to delineate the role of the IERSR in the pathobiology of the motor-neuron diseases. Both RO1 and R21 grant applications to support these work are at various stages of review process.

Publications from Harvard Catalyst Profiles

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  • Liu F, Dai S, Feng D, Qin Z, Peng X, Sakamuri SSVP, Ren M, Huang L, Cheng M, Mohammad KE, Qu P, Chen Y, Zhao C, Zhu F, Liang S, Aktas BH, Yang X, Wang H, Katakam PVG, Busija DW, Fischer T, Datta PK, Rappaport J, Gao B, Qin X. Distinct fate, dynamics and niches of renal macrophages of bone marrow or embryonic origins. Nat Commun 2020; 11:2280. PubMed
  • Aktas BH, Upcin B, Henke E, Padmasekar M, Qin X, Ergün S. The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells. Stem Cells Int 2019; 2019:1608787. PubMed
  • Nandigama R, Upcin B, Aktas BH, Ergün S, Henke E. Restriction of drug transport by the tumor environment. Histochem Cell Biol 2018; 150:631-648. PubMed
  • Burwick N, Aktas BH. The eIF2-alpha kinase HRI: a potential target beyond the red blood cell. Expert Opin Ther Targets 2017; 21:1171-1177. PubMed
  • Yefidoff-Freedman R, Fan J, Yan L, Zhang Q, Dos Santos GRR, Rana S, Contreras JI, Sahoo R, Wan D, Young J, Dias Teixeira KL, Morisseau C, Halperin J, Hammock B, Natarajan A, Wang P, Chorev M, Aktas BH. Development of 1-((1,4-trans)-4-Aryloxycyclohexyl)-3-arylurea Activators of Heme-Regulated Inhibitor as Selective Activators of the Eukaryotic Initiation Factor 2 Alpha (eIF2α) Phosphorylation Arm of the Integrated Endoplasmic Reticulum Stress Response. J Med Chem 2017. PubMed
  • Aktas BH, Bordelois P, Peker S, Merajver S, Halperin JA. Depletion of eIF2·GTP·Met-tRNAi translation initiation complex up-regulates BRCA1 expression in vitro and in vivo. 2015. PubMed
  • Papadopoulos E, Jenni S, Kabha E, Takrouri KJ, Yi T, Salvi N, Luna RE, Gavathiotis E, Mahalingam P, Arthanari H, Rodriguez-Mias R, Yefidoff-Freedman R, Aktas BH, Chorev M, Halperin JA, Wagner G. Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. Proc Natl Acad Sci U S A 2014; 111:E3187-95. PubMed
  • Mahalingam P, Takrouri K, Chen T, Sahoo R, Papadopoulos E, Chen L, Wagner G, Aktas BH, Halperin JA, Chorev M. Synthesis of rigidified eIF4E/eIF4G inhibitor-1 (4EGI-1) mimetic and their in vitro characterization as inhibitors of protein-protein interaction. J Med Chem 2014. PubMed
  • Takrouri K, Chen T, Papadopoulos E, Sahoo R, Kabha E, Chen H, Cantel S, Wagner G, Halperin JA, Aktas BH, Chorev M. Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors. Eur J Med Chem 2014; 77:361-77. PubMed
  • Yefidoff-Freedman R, Chen T, Sahoo R, Chen L, Wagner G, Halperin JA, Aktas BH, Chorev M. 3-substituted indazoles as configurationally locked 4EGI-1 mimetics and inhibitors of the eIF4E/eIF4G interaction. Chembiochem 2014; 15:595-611. PubMed
  • Chen T, Takrouri K, Hee-Hwang S, Rana S, Yefidoff-Freedman R, Halperin J, Natarajan A, Morisseau C, Hammock B, Chorev M, Aktas BH. Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase. J Med Chem 2013; 56:9457-70. PubMed
  • Denoyelle S, Chen T, Yang H, Chen L, Zhang Y, Halperin JA, Aktas BH, Chorev M. Synthesis and SAR study of novel 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as potent eIF2·GTP·Met-tRNAiMet ternary complex inhibitors. Eur J Med Chem 2013; 69:537-53. PubMed
  • Aktas BH, Qiao Y, Ozdelen E, Schubert R, Sevinc S, Harbinski F, Grubissich L, Singer S, Halperin JA. Small-Molecule targeting of translation initiation for cancer therapy. 2013; 4:1606-17. PubMed
  • Bai H, Chen T, Ming J, Sun H, Cao P, Fusco DN, Chung RT, Chorev M, Jin Q, Aktas BH. Dual activators of protein kinase R (PKR) and protein kinase R-like kinase PERK identify common and divergent catalytic targets. Chembiochem 2013; 14:1255-62. PubMed
  • Ziegeler G, Ming J, Koseki JC, Sevinc S, Chen T, Ergun S, Qin X, Aktas BH. Embryonic lethal abnormal vision-like HuR-dependent mRNA stability regulates post-transcriptional expression of cyclin-dependent kinase inhibitor p27Kip1. J Biol Chem 2010; 285:15408-19. PubMed
  • Wu G, Chen T, Shahsafaei A, Hu W, Bronson RT, Shi GP, Halperin JA, Aktas H, Qin X. Complement Regulator CD59 Protects Against Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice. Circulation 2010; 121:1338-46. PubMed
  • Ozel Demiralp D, Aktas H, Akar N. The effect of plasminogen activator inhibitor-1 -675 4G/5G polymorphism on PAI-1 gene expression and adipocyte differentiation. Clin. Appl. Thromb. Hemost. 2008; 14:438-46. PubMed
  • Hyberts SG, Heffron GJ, Tarragona NG, Solanky K, Edmonds KA, Luithardt H, Fejzo J, Chorev M, Aktas H, Colson K, Falchuk KH, Halperin JA, Wagner G. Ultrahigh-resolution (1)H-(13)C HSQC spectra of metabolite mixtures using nonlinear sampling and forward maximum entropy reconstruction. J Am Chem Soc 2007; 129:5108-16. PubMed
  • Moerke NJ, Aktas H, Chen H, Cantel S, Reibarkh MY, Fahmy A, Gross JD, Degterev A, Yuan J, Chorev M, Halperin JA, Wagner G. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 2007; 128:257-67. PubMed
  • Gelev V, Aktas H, Marintchev A, Ito T, Frueh D, Hemond M, Rovnyak D, Debus M, Hyberts S, Usheva A, Halperin J, Wagner G. Mapping of the auto-inhibitory interactions of protein kinase R by nuclear magnetic resonance. J Mol Biol 2006; 364:352-63. PubMed
  • Chen H, Fan YH, Natarajan A, Guo Y, Iyasere J, Harbinski F, Luus L, Christ W, Aktas H, Halperin JA. Synthesis and biological evaluation of thiazolidine-2,4-dione and 2,4-thione derivatives as inhibitors of translation initiation. Bioorg Med Chem Lett 2004; 14:5401-5. PubMed
  • Natarajan A, Guo Y, Harbinski F, Fan YH, Chen H, Luus L, Diercks J, Aktas H, Chorev M, Halperin JA. Novel arylsulfoanilide-oxindole hybrid as an anticancer agent that inhibits translation initiation. J Med Chem 2004; 47:4979-82. PubMed
  • Aktas H, Halperin JA. Translational regulation of gene expression by omega-3 fatty acids. J Nutr 2004; 134:2487S-2491S. PubMed
  • Fan YH, Chen H, Natarajan A, Guo Y, Harbinski F, Iyasere J, Christ W, Aktas H, Halperin JA. Structure-activity requirements for the antiproliferative effect of troglitazone derivatives mediated by depletion of intracellular calcium. Bioorg Med Chem Lett 2004; 14:2547-50. PubMed
  • Natarajan A, Fan YH, Chen H, Guo Y, Iyasere J, Harbinski F, Christ WJ, Aktas H, Halperin JA. 3,3-diaryl-1,3-dihydroindol-2-ones as antiproliferatives mediated by translation initiation inhibition. J Med Chem 2004; 47:1882-5. PubMed
  • Aktas H, Leibfried-Rutledge ML, First NL. Meiotic state of bovine oocytes is regulated by interactions between cAMP, cumulus, and granulosa. 2003; 65:336-43. PubMed
  • Qin X, Krumrei N, Grubissich L, Dobarro M, Aktas H, Perez G, Halperin JA. Deficiency of the mouse complement regulatory protein mCd59b results in spontaneous hemolytic anemia with platelet activation and progressive male infertility. Immunity 2003; 18:217-27. PubMed