Therapeutics

Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy.Citri, A. et al. EMBO J. 21, 2407–2417 (2002)

The receptor tyrosine kinase ERBB2 is overexpressed in many cancers, and is an important target for cancer treatment. Drugs that inhibit the kinase activity are proving effective, and Yosef Yarden and colleagues have shown that some tyrosine kinase inhibitors, notably CI-1033, also promote ubiquitylation, and hence degradation, of ERBB2, to further improve the efficacy of the drug.

Tumour suppressors

Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo.Ji, K. et al. Cancer Res. 62, 2715–2720 (2002)

Deletions in the human chromosome 3p21.3 region have been associated with lung cancers, but the region contains more than 25 genes, making it difficult to determine which ones are tumour suppressors. Ji et al. used adenoviral vectors to assess the tumour-suppressive capability of each gene in vitro. 101F6, NPRL2 and FUS1 induced human lung cancer cell-specific apoptosis, and their intratumoral injection suppressed lung cancer in mouse models.

Oncogenes

Amplification of PPM1D in human tumours abrogates p53 tumour suppressor activity.Bulavin, D. V. et al. Nature Genet. 31, 210–215 (2002)

Oncogenic properties of PPM1D located within a breast cancer amplification epicentre at 17q23.Li, J. et al. Nature Genet. 31, 133–134 (2002)

In response to oncogenic RAS activation, p38 mitogen-activated protein kinase can phosphorylate and activate p53. The phosphatase PPM1D — which is amplified in 11% of human breast tumours — blocks this phosphorylation and prevents the senescence response that protects cells from the oncogenic effects of RAS.

Therapeutics

Targeting Raf-1 gene expression by a DNA enzyme inhibits juvenile myelomonocytic leukaemia cell growth.Iversen, P. E. et al. Blood 99, 4147–4153 (2002)

Children with juvenile myelomonocytic leukaemia (JMML) are resistant to standard chemotherapy. A potential therapeutic strategy for JMML has been developed that blocks an autocrine loop: cytokines activate the RAS–RAF–mitogen-activated protein kinase (MAPK) pathway and cause JMML cells to secrete more cytokines. A DNA enzyme that specifically cleaves RAF1 mRNA blocked cytokine production in JMML cells but had no effect on normal bone-marrow cells. Continuous infusion of the enzyme prevented the growth of JMML cells in immunodeficient mice.