Telomeres

A highly selective telomerase inhibitor limiting cancer cell proliferation. Damm, K. et al. EMBO J. 20, 6958–6658 (2001) [PubMed]

Telomerase — the enzyme responsible for telomere maintenance and hence replicative potential — is expressed in most human cancers, but not in normal somatic tissue, making it a good candidate for anticancer therapy. Damm et al. have identified several compounds that inhibit telomerase, resulting in telomere shortening. One of these, BIBR1532, also limits the tumorigenic potential of tumour cells in a mouse xenograft model, without serious side effects.

Mouse models

Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Jackson, E. L. et al. Genes Dev. 15, 3243–3248 (2001)

Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Fisher, G. H. et al. Genes Dev. 15, 3249–3262 (2001)

Oncogenic KRAS mutations can give rise to lung adenocarcinomas, but where do these tumours arise, and is KRAS also important for tumour maintenance? Two new mouse models address these questions. Jackson and colleagues can switch on oncogenic Kras in a few cells by administering a vector encoding an enzyme that edits a stop codon out of an engineered KRas gene. This has allowed them to identify a progenitor-like cell as the cell of origin for lung adenocarcinoma. Fisher and colleagues can switch Kras on and off at will. In this model, tumours regress rapidly by apoptosis when Kras expression is switched off, even in the absence of p53, Ink4a or Arf. This has implications for therapy as it indicates that blocking the RAS pathway, even in advanced tumours, could lead to apoptosis of tumour cells.

Structural biology

A novel pH-dependent destabilization of a mutant p53 tetramer leads to tumorigenesis. DiGiammarino, E. L. et al. Nature Struct. Biol. 9, 12–16 (2002) [PubMed]

These authors undertook a structural analysis of a mutant form of p53 isolated from children in southern Brazil who have a high incidence of adrenocortical carcinoma. This mutant p53 contains an Arg-to-His mutation at amino acid 337 in the tetramerization domain, causing p53 to lose stability and become highly pH sensitive. The authors propose that the elevated pH in the developing adrenal gland might destabilize p53 and cause it to lose its tumour-suppressor function, leading to adrenocortical cancer.