Poster Presentation 26th Lorne Cancer Conference 2014

The role of tumour suppressor TRIM35 in regulating TGF-ß signaling  (#275)

Joanne van Vuuren 1 , Louise N Winteringham 1 , Jennifer G Beaumont 1 , Warren Alexander 2 , Peter S Klinken 1
  1. Western Australia Institute for Medical Research, Perth, WA, Australia
  2. Walter and Eliza Hall Institute, Melbourne, Victoria, Australia

Haemopoietic Lineage switch 5 (Hls5)/Trim35 belongs to the tripartite motif (TRIM) family of proteins that share several conserved structural domains including a Ring-finger, B-box and coiled-coil domain (RBCC) [1]. A number of TRIM proteins have been identified as E3 ubiquitin ligases regulating various cellular processes such as apoptosis, cell cycle progression and viral response [2-4].

Several members of the TRIM family have been implicated in various pathologies including cancer. One of the best known examples is TRIM19, otherwise known as promyelocytic leukaemia (PML), which is translocated specifically in acute promyelocytic leukaemia (APL) [5].

We identified Trim35 as a regulator of erythroid cell differentiation and have confirmed that it functions as an E3 ubiquitin ligase that can regulate the erythroid transcription factor GATA-1.  Trim35 is localized on chromosome 8p21, a region that contains a cluster of tumour suppressor genes often deleted in cancer [6]. Furthermore, over-expression of Trim35 in HeLa cells resulted in inhibition of their tumorigenicity.

We and others have shown that Trim35 interacts with a number of proteins involved in many different processes including cell-cycle regulation. Therefore, it is likely that Trim35 has a role in regulating a number of different pathways.

My research focuses on the TGF-β signaling pathway. TGF-β is known to be involved in a large variety of processes including cell-cycle arrest, apoptosis and differentiation and is considered to play an important role in many different cancers [7-8]. TGF-β signaling is facilitated by regulatory SMAD proteins that mediate changes in gene expression. We have shown that Trim35 can interact with key components of the TGF-β pathway including the regulatory SMAD1 and SMAD3 proteins as well as with the cooperative SMAD4 and we are now focusing on understanding how this interaction will affect TGF-β signaling. 

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  8. Kang, Y., et al., Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proceedings of the National Academy of Sciences of the United States of America, 2005. 102(39): p. 13909-13914