Research Highlights

Short, accessible synopses of recent important articles concerning signalling pathways.

June 2007

• Breast cancer: AKT1 wears many hats

  

  The anti-apoptotic serine threonine kinase AKT1 is often activated in human cancers, and might contribute to tumour progression and metastasis. However, previous studies, primarily in cell lines, have shown conflicting results. Therefore, Richard Pestell and colleagues used Akt1-null mice to examine the role of AKT1 in a mouse model of breast cancer.

  Original research paper Nature Reviews Cancer 7 407 doi:10.1038/nrc2157

• Senescence: Arrest me!

  

  Cellular senescence, the permanent arrest of cells from division, as a tumour-suppressive mechanism is not a new concept, but has suffered from a lack of concrete in vivo evidence. This evidence has recently surfaced, and is now given more weight by three new papers.

  Original research paper Nature Reviews Cancer 7 401 doi:10.1038/nrc2159

• Hypoxia: Opposing effects

  

  The expression of hypoxia-inducible factors (HIFs) is common in cancer. HIF2, but not HIF1, promotes the growth of renal-cell carcinomas (RCCs) that are von Hippel-Lindau (VHL)-deficient, and these tumours maintain HIF2 but many lose HIF1 expression during progression. M. Celeste Simon and colleagues now show that at least one reason for the loss of HIF1 but the retention of HIF2 is that they have opposing effects on MYC.

  Original research paper Nature Reviews Cancer 7 402 - 403 doi:10.1038/nrc2151

• Therapy: Addicted to repair

  

  The rationale for developing anticancer drugs that target DNA damage response (DDR) pathways has been strengthened by the encouraging results from using inhibitors of poly(ADP-ribose) polymerase 1 (PARP1), a member of the base excision repair (BER) pathway, to selectively kill BRCA1- or BRCA2-deficient tumour cells, which are incapable of activating homologous recombination DNA repair pathways. Such strategies rely on identifying DDR pathways that are crucial to the maintenance of genomic stability in cells that are already compromised for at least one DDR pathway. This prompted Alan D'Andrea and colleagues to identify DDR pathways that compensate for the loss of the Fanconi anaemia (FA) DDR pathway.

  Original research paper Nature Reviews Cancer 7 402 - 403 doi:10.1038/nrc2155

• Tumour suppressors: Detaining division

  

  The mitogen-activated protein kinase MAPK14 (also known as p38) is associated with inflammatory and stress responses, but its contribution to tumorigenesis has remained unclear. Two groups now show that MAPK14 inhibits cell proliferation and tumorigenesis in the liver and lungs.

  Original research paper Nature Reviews Cancer 7 404 - 405 doi:10.1038/nrc2156

• Tumorigenesis: Taking the hallmark?

  

  About 70% of all cancers show overexpression of the Myc family of transcription factors. A hallmark of Myc-mediated tumorigenesis is thought to be its ability to accelerate proliferation by downregulating the tumour suppressor p27, a cyclin-dependent kinase inhibitor. John Cleveland and colleagues have now identified a Myc-dependent pathway that is required to downregulate p27 and hence propagate lymphomagenesis.

  Original research paper Nature Reviews Cancer 7 404 - 405 doi:10.1038/nrc2161

• Drug resistance: Alternative routes

  

  Two tyrosine kinase inhibitors (TKIs) — gefitinib (Iressa) and erlotinib (Tarceva) — are used to treat non-small-cell lung cancers (NSCLCs) with activating mutations of the epidermal growth factor receptor (EGFR). However, following an initial positive response most tumours become resistant to the drugs; in 50% of cases this occurs because a secondary EGFR mutation arises. Now Jeffrey Engelman and colleagues have identified another route, which involves the amplification of the receptor tyrosine kinase MET. This bypasses EGFR inhibition and confers resistance to gefitinib, reactivating the EGFR signalling pathway through the EGFR family member ERBB3.

  Original research paper Nature Reviews Cancer 7 405 doi:10.1038/nrc2158

• Immune regulation: Terminating inflammatory responses

  

  The transcription factor NF-B (nuclear factor-B) is an important regulator of inflammatory responses. However, NF-B activation must be terminated in a timely manner as excessive inflammation can cause tissue damage and disease. Now, Takashi Tanaka and colleagues report a new way of terminating NF-B activation: PDLIM2 (a nuclear protein containing a PDZ domain and a LIM domain) acts as an E3 ubiquitin ligase, promoting ubiquitylation of the p65 subunit of NF-B and leading to nuclear degradation of p65.

  Original research paper Nature Reviews Immunology 7 414 - 415 doi:10.1038/nri2104

• Neuronal migration: Signalling retreat

  

  Migrating neurons navigate their environment by responding to various extracellular guidance cues. Coordination of the behaviour of the growth cone and the translocation of the cell body is essential, yet the means by which this is achieved are unknown. Poo and colleagues now reveal a mechanism by which growth cones can relay such guidance signals to the cell body.

  Original research paper Nature Reviews Neuroscience 8 410 - 411 doi:10.1038/nrn2157

Catching up to the speed of signaling



A simple, continuous quench-flow system allows quantitative analysis of very early cellular signaling events.

Original research paper Nature Methods 4 476 doi:10.1038/nmeth0607-476