Therapeutics

Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1 , potentiates cancer chemotherapy. Muller, A. J., DuHadaway, J. B., Donover, S., Sutanto-Ward, E. & Prendergast, G. C. Nature Med. 13 Feb 2005 (10.1038/nm1996)

Increased expression of the immunomodulatory enzyme indoleamine 2,3 dioxygenase (IDO) mediates T-cell-mediated immune escape in tumour cells. Muller et al. report that IDO expression is regulated by the signalling protein BIN1 — tumours grown in Bin1-null mice are resistant to T-cell-mediated immunity. In a mouse model of breast cancer, the authors show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to induce regression of established tumours.

Viral oncogenesis

The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. McCormick, C. & Ganem, D. Science 307, 739–741 (2005)

Cytokine production is an important factor in Kaposi's sarcoma herpesvirus (KSHV)-associated tumour progression. McCormick and Ganem show that Kaposin, a latent KSHV gene product, increases cytokine production by stabilizing the mRNAs that encode them. These findings reveal a new mechanism by which viruses can selectively modulate mRNA turnover and mediate tumorigenesis.

Tumour progression

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Selak, M. A. et al. Cancer Cell 7, 77–85 (2005)

Succinate dehydrogenase (SDH) is a mitochondrial tricarboxylic acid (TCA)-cycle enzyme. Loss of SDH activity or expression is associated with renal-cell, gastric and colon cancers. Selak et al. show that SDH downregulation leads to the accumulation of succinate, a TCA-cycle metabolite, in the cytosol. There, succinate inhibits the hypoxia-inducible factor-1α (HIF1α) prolyl hydroxylase, resulting in HIF1α stabilization under normoxic conditions. This leads to increased expression of genes that promote tumour angiogenesis, metastasis and glycolysis.

Genetics

The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA–ssDNA junction. Yang, H., Li, Q., Fan, J., Hollman, W. K. & Pavletich, N. P. Nature 433, 653–657 (2005)

Yang et al. describe the function of BRH2, a homologue of the tumour suppresssor BRCA2. They explain how BRH2 recruits the repair protein RAD51 to repair double-stranded DNA breaks. BRH1 acts preferentially at a junction between double-stranded and single-stranded DNA, and the authors propose that defects in this activity might lead to loss of the DNA-repair capacity of BRCA2-associated tumours.