Poster Presentation 27th Lorne Cancer Conference 2015

Post-translational regulation of the BCL-2 family protein A1/BFL-1 (#124)

Margs S Brennan 1 2 , Andrew Kueh 1 2 , Lin Tai 2 , Ingolf Berberich 3 , Andreas Strasser 1 2 , Marco Herold 1 2
  1. Department of Medical Biology, University of Melbourne, Parkville 3052, VIC, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia
  3. Institute for Immunology and Virology, University of Wuerzburg, Wuerzberg, Germany

Apoptosis is a fundamental process by which multicellular organisms remove unwanted or dangerous cells and maintain tissue homeostasis. Murine A1 and the human homologue BFL-1 are pro-survival BCL-2 family proteins expressed almost exclusively in the haematopoietic system where apoptosis is crucial for the development, and maintenance of a healthy immune system. A1/BFL-1 has been implicated in many leukaemias and lymphomas as well as a small number of carcinomas. Furthermore, within these cancers high levels of A1/BFL1 have been correlated with treatment-refractory disease and poor patient outcomes1. In addition, it has been shown that enforced expression of a truncated version of BFL-1 in a xenograft mouse model of human leukaemia/lymphoma substantially accelerated tumour growth2. The c-terminus of A1/BFL-1 is important in its post-translational regulation by ubiquitylation, suggesting that the ubiquitin pathway of degradation constitutes an important tumour suppressing mechanism in the regulation of A1/BFL-13, 4. To date the ubiquitin E3-ligase(s) responsible for A1/BFL1 ubiquitylation remains unknown. Preliminary work by our collaborators identified the HectD1 E3 ligase as a potential candidate ubiquitinating A1/BFL-1. While HectD1 is not well studied, it is known that homozygous loss of HectD1 causes neural tube closure defects and exencephaly in mice5.  My work is centralised around investigating whether HectD1 is a critical regulator of A1 protein stability and function. To answer this question I examined the consequences of loss of HectD1 on A1 stability in vitro and in vivo. The evidence I have collected suggests that loss of HectD1 alone does not affect A1 stability, but may regulate apoptosis and play a role in some thymic and peripheral T lymphocyte subsets and cells of the myeloid lineage.

1.         Vogler M. (2012) BCL2A1: the underdog in the BCL2 family. Cell Death and Differentiation. 19(1):67-74.

2.         Fan G, Simmons M, Ge S, Dutta Simmons J, Kucharczak J, Ron Y, Weissmann D, Chen C-C, Mukherjee C, White E et al. (2010) Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma. Blood. 115(17):3559-3569.

3.         Herold M, Zeitz J, Pelzer C, Kraus C, Peters A, Wohlleben G, Berberich I. (2006) The stability and anti-apoptotic function of A1 are controlled by its C terminus. Journal of biological chemistry. 281(19):13663-13671.

4.         Kucharczak JF, Simmons MJ, Duckett CS, Gélinas C. (2005) Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor. Cell Death and Differentiation. 12(9):1225-1239.

5.         Zohn I, Anderson K, Niswander L. (2007) The Hectd1 ubiquitin ligase is required for development of the head mesenchyme and neural tube closure. Developmental biology. 306(1):208-221.