The plenary session will begin with a welcome from the conference co-chairs Professor Anthony Cheetham FRS, Treasurer and Vice-President of the Royal Society and Professor CNR Rao FRS, Chairman of the Scientific Advisory Council to the Prime Minister of India.
Impaired apoptosis is a critical step in the development of cancer and a major impediment to effective therapy. It is now ~ 25 years since the discovery in our laboratory that Bcl-2, the oncoprotein activated by chromosome translocation in human follicular lymphoma, inhibits cells from undergoing apoptosis in response to cytokine deprivation (Vaux et al., 1988). Since that time, there has been an explosion of knowledge about the mechanism of apoptosis and this knowledge is now leading to new approaches to cancer therapy.
A score or so Bcl-2 relatives have been identified in mammalian cells. The closest homologs (Bcl xL, Bcl-w, Mcl-1 and A1) are also anti-apoptotic but Bax and Bak are instead pro-apoptotic, despite strong sequence and structural homology. More distant pro-apoptotic family members, the ‘BH3-only proteins’, are largely unrelated, apart from the signature BH3 (Bcl-2 homology region 3) domain that is essential for their killing function. Together, the Bcl-2 family of proteins constitutes a life/death switch that arbitrates whether or not a cell should activate apoptosis in response to diverse intracellular stresses. Cytotoxic signals activate “BH3-only” proteins, which bind avidly to a hydrophobic groove on Bcl-2 and its pro-survival homologs, thereby neutralizing their capacity to prevent activation of Bax or Bak. Certain BH3-only proteins, most notably Bim, tBid and Puma, can also directly activate Bax and Bak. Once activated, Bax and Bak oligomerise and permeabilise the outer mitochondrial membrane, thereby releasing cytochrome c to trigger the cascade of caspase activation that sets in train the demise of the ...
Using mouse models, we have shown that over-expression of Bcl-2 or Mcl-1, or loss of the BH3-only protein Bim or certain other BH3-only proteins, exacerbates a variety of lymphoid and myeloid neoplasias. Our recent preclinical studies suggest that small molecules mimicking BH3 domains will be effective cancer therapeutics.
Lead image: Glass House at the Lalbagh Botanical Garden in BangaloreDownload calendar
Professor Alexander Halliday FRS Head of the Mathematical, Physical and Life Sciences Division, University of Oxford
Professor Raghavendra Gadagkar President of the Indian National Science Academy
Professor Suzanne Cory FRS Honorary Distinguished Professorial Fellow, Walter and Eliza Hall Institute of Medical Research (Australia)
Professor Veerabhadran Ramanathan Distinguished Professor, Scripps Institution of Oceanography (USA)