Tumour suppressors

HLTF gene silencing in human colon cancer.Moinova, R. et al. Proc. Natl Acad. Sci. USA 99, 4562–4567 (2002)

Expression of helicase-like transcription factor (HLTF) — a member of the SWI/SNF family of chromatin-remodelling enzymes, which have been shown to be disrupted in cancer — is lost in ∼30% of colon cancer cell lines. This loss is accompanied by promoter methylation, and is restored following addition of 5-azacytidine, a demethylating agent. Interestingly, the HLTF promoter is not methylated in breast or lung cancer, so HLTF might specifically suppress colon cancer. Consistent with this, its transfection into HLTF-deficient cell lines suppresses colony growth.

P53 regulation

Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization.Li, M. et al. Nature 416, 648–653 (2002)

To function as a tumour suppressor, p53 must first be freed from the clutches of MDM2, a ubiquitin ligase that targets p53 for degradation. Li et al. have used mass spectrometry to identify p53-interacting proteins, and have discovered herpesvirus-associated ubiquitin-specific protease (HAUSP). HAUSP can deubiquitylate — and therefore stabilize — p53, even in the presence of MDM2. Accumulation of p53 results in growth arrest and apoptosis. HAUSP might therefore act as a tumour suppressor, by stabilizing p53.

Mouse models

Nf2 gene inactivation in arachnoidal cells is rate limiting for meningioma development in the mouse.Kalamarides, M. et al. Genes Dev. 16, 1060–1065 (2002)

Tumours of the membranes that cover the brain, known as meningiomas, are a common affliction of people with neurofibromatosis type 2, which is caused by inactivation of the NF2 gene. However, Nf2−/− mice don't develop meningiomas. Michel Kalamarides and colleagues have developed the first genetically modified mouse model of meningioma by knocking out Nf2 in a small number of meningeal cells.

Therapeutics

ErbB2 is essential in the prevention of dilated cardiomyopathy.Crone, S. et al. Nature Med. 8, 459–465 (2002)

Herceptin (trastuzumab) — a humanized monoclonal antibody specific for the extracellular domain of the receptor tyrosine kinase ERBB2 — is used to treat breast cancers that overexpress ERBB2. Some patients that take this drug, however, experience cardiac dysfunction. To investigate the role of ErbB2 in the adult heart, mice with a ventricular-restricted deletion of ErbB2 were generated. These mice developed many features of dilated cardiomyopathy, indicating that ErbB2 function is required for normal cardiomyocyte function. Strategies to prevent cardiac dysfunction must therefore be developed for patients who take Herceptin.