Reflections under a jacaranda tree

  1. For those who are curious to know the reason behind the title of this interview, please refer to a video-clip from the interview 

  2. This interview took place on 05/06/2015 together with Andrea Mameli at the Hotel Panorama in Cagliari, whom we thank for their hospitality. A sincere thanks also goes to Saverio Gaeta and to the organisers of the Leggendo Metropolitano festival who made this meeting possible 

  3. A. Ciechanover, Early work on the ubiquitin proteasome system, an interview with Aaron Ciechanover, Cell Death and Differentiation, 12, 1167–1177, 2005 

  4. Bortezomib was approved by the FDA in 2003 as a treatment for multiple myeloma in refractory patients, in 2005 as a second-line therapy, in 2008 as first-line therapy 

  5. For a short review of the topic see for instance Naidoo J, Page DB, and Wolchok JD, Immune modulation for cancer therapy, BJC, 111, 12:2214-2219, 2014 

  6. Gerlinger M, Rowan AJ, Horswell S, Larkin J et al, Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing, NEJM, 366, 10:883-892, 2012 

  7. Especially solid tumors. See the Technical corner 

  8. Vogelstein B, Kinzler KW, Cancer genes and the pathways they control, Nature Medicine, 10, 8:789-799, 2004 

  9. After personalized, predictive, preventive, and participatory: this is “P4 medicine”, a very popular term coined by Leroy Hood in 2005 

  10. Protein degradation is a fundamental task for eukaryotes. Inside cells, proteins homeostasis results from the opposite actions of synthesis and degradation. Proteins typical half-lives vary widely, from minutes to several days: differential rates of protein degradation is a basis of cell regulation. Regulatory molecules, such as transcription factors, are rapidly degraded, as their rapid turnover allows prompt changes to external stimuli. Degradation of other proteins in response to specific signals is another well-known mechanism for regulating the intracellular enzyme activity. Another necessary task is the destruction of faulty or damaged proteins, in order to eliminate the consequences of errors made during protein synthesis. In eukaryotes two major pathways are involved in protein degradation: the ubiquitin-proteasome system and the lysosomal proteolysis. See, for instance, Cooper GM, The Cell: A Molecular Approach. 2nd edition, Sunderland (MA) Sinauer Associates, 2000. 

  11. Ciechanover A, Elias S, Heller H, Ferber S, and Hershko A, Characterization of the heat-stable polypeptide of the ATP-dependent proteolytic system from reticulocytes, J. Biol. Chem., 255, 16:7525-7528, 1980 

  12. Wilkinson KD, Urban MK, and Haas AL, Ubiquitin is the ATP-dependent proteolysis factor I of rabbit reticulocytes, J. Biol. Chem., 255, 16:7529-7532, 1980 

  13. Hershko A, and Ciechanover A, The ubiquitin system, Annu. Rev. Biochem., 67:425–79, 1998 

  14. See Nath D and Shadan S, The ubiquitin system, Nature Insight, 458, 7237:421-467, 2009, and references therein 

  15. See Table 1 in Micel LN, Tentler JJ, Smith PG, and Eckhardt SG, Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies, J Clin Oncol, 31, 9:1231-1238, 2013 

  16. For a detailed analysis of molecular mechanisms of bortezomib see Cvek B, and Dvorak Z, The ubiquitin-proteasome system (UPS) and the mechanism of action of bortezomib, Curr Pharm Des, 17:1483-99, 2011 

  17. Roughly speaking, the ratio of the dose of drug that causes adverse effects divided by the dose that leads to the desired pharmacological effect 

  18. Dick LR, and Fleming PE, Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy, Drug Discovery Today, 15, 5/6:243-249, 2010 

  19. Ruschak AM, Slassi M, Kay LE, and Schimmer AD, Novel Proteasome Inhibitors to Overcome Bortezomib Resistance, JNCI J Natl Cancer Inst, 103, 13:1007-1017, 2011