Cancer genetics

HIF overexpression correlates with biallelic loss of fumerate hydratase in renal cancer: novel role of fumerate in regulation of HIF stability. Isaacs, J. S. et al. Cancer Cell 8, 143–153 (2005)

Fumerate hydratase (FH) converts fumerate to malate. This paper shows that increased levels of fumerate function as a competitive inhibitor of the prolyl hydroxylase that labels hypoxia-inducible factor (HIF) for degradation by the von Hippel–Lindau (VHL)-containing ubiquitin-ligase complex. Increased levels of fumerate do not affect VHL function, so the development of renal tumours in patients with familial FH mutations is HIF-dependent, but VHL-independent.

Apoptosis

Clusterin inhibits apoptosis by interacting with activated Bax. Zhang, H. et al. Nature Cell Biol. 21st August (10.1038/ncb1291)

This paper shows that the glycoprotein clusterin inhibits the pro-apoptotic protein BAX. In response to chemotherapeutic drugs, BAX undergoes a conformational change into an active form, but clusterin prevents oligomerization of activated BAX, which is essential for its pro-apoptotic function. Consequently, clusterin can promote MYC-induced transformation by inhibiting MYC-induced apoptosis, demonstrating that clusterin is a valid anticancer target.

Tumorigenesis

Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Hemann, M. T. et al. Nature 436, 807–811 (2005)

Two common mutant MYC alleles found in human Burkitt lymphoma uncouple the capacity of MYC to induce both apoptosis and proliferation. The mutant MYC proteins activate proliferation and still activate p53 by triggering the activation of ARF, but unlike wild-type MYC, do not induce activation of the BH3-only, pro-apoptotic protein BIM. So, parallel apoptotic pathways function to suppress MYC-induced transformation and disabling a p53-independent apoptosis pathway is enough for tumour cells to evade p53 action.

Therapeutics

Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. Takeshita, F. et al. Proc. Natl Acad. Sci. USA 9 Aug (10.1073/pnas.0501753102)

The expression of genes involved in certain cancers can be reduced by treatment with short interfering RNAs (siRNAs), but unwanted immune reactions have hindered delivery strategies. This paper shows that siRNAs function successfully in mice when delivered on modified collagen molecules rather than viral or lipid vectors. When targeted against a bioluminescence marker there was a 90% decrease in luminescence; when targeted against two prostate cancer genes, tumour growth was reduced throughout the body.