Sylvester Comprehensive Cancer Center

UM/Sylvester Scientist Identifies Proteins Linked to Inflammation and Cancer

04.29.2008

Edward W. Harhaj, Ph.D., assistant professor in the Department of Microbiology and Immunology at the Sylvester Comprehensive Cancer Center, co-authored a study that identified a complex set of proteins essential in limiting inflammation that is targeted by a viral protein, which in turn, causes a type of cancer. The study has been published in the journal Nature Immunology.

Dr. Harhaj’s lab has been studying the mechanisms of oncogenesis of the human T cell leukemia virus type I (HTLV-I). Specifically, his research has focused on “Tax”, which is an important viral regulatory protein. Tax activates a cellular transcription factor called NF-kB. That activation is tightly controlled and is normally activated transiently in response to inflammatory cytokines, regulatory proteins, produced during an infection with pathogens. However, many cancers, including HTLV-I transformed cells, exhibit persistent NF-kB activation. The reason for that is unclear.

Initially, Dr. Harhaj began looking at the normal function of a cellular Tax interacting protein known as TAX1BP1. He determined that TAX1BP1 was essential in restricting NF-kB activation in response to inflammatory cytokines. Cells that did not have TAX1BP1 demonstrated persistent NF-kB activation.

In this most recent study, Dr. Harhaj and his team expanded those findings by identifying the exact areas of TAX1BP1 that are necessary for its ability to inhibit NF-kB. The scientists found that two small motifs within TAX1BP1 known as ‘PPXY’ were important for its function. TAX1BP1 recruits a specific enzyme via the ‘PPXY’ motifs, in this case, the E3 ligase named ‘Itch’. That enzyme then connects with A20, another enzyme that is a critical regulator of inflammation. The scientists determined that A20 requires the enzymatic action of ‘Itch’, and cannot function without it.

The research showed that cells not containing Itch were unable to stop NF-kB signaling, similar to cells lacking TAX1BP1. The scientists determined that this complex of proteins consisting of TAX1BP1, Itch and A20 are essential in limiting inflammatory signaling pathways and inflammation. The original Tax oncoprotein of human T cell leukemia virus type 1 (HTLV-1) somehow targets this trio for inactivation by disrupting the interaction among TAX1BP1, ‘Itch’ and A20. The disruption likely contributes to persistent NF-kB signaling, possibly leading to the development of cancer.

The next phase of Dr. Harhaj’s research will take a closer look at the reasons why A20 requires the ‘Itch’ enzyme and how Tax disrupts this interaction. In addition, it is known that different cancers, including breast cancer, have high levels of A20, and A20 and plays a critical role in the survival of these cells. Future studies will examine the expression of A20, TAX1BP1 and ‘Itch’ in various cancers and determine how these proteins provide a survival advantage for those malignant cells.

E-mail a Friend