Tumour suppression

LKB1 signalling in mesenchymal cells required for suppression of gastrointestinal polyposis Katajisto, P. et al. Nature Genet. 2 Mar 2008 (doi 10.1038/ng.98)

Germline mutations in STK11, the gene encoding the tumour suppressor LKB1, are present in patients with Peutz–Jeghers syndrome (PJS). Pekka Katajisto and colleagues have found that the epithelial polyps that develop in these patients might arise because of defects in transforming growth factor β (TGFβ) signaling in mesenchymal cells. By engineering either biallelic or monoallelic Stk11 loss in mesenchymal cells in mice, the authors found that these mice developed gastrointestinal polyps that were indistinguishable from those arising in other mouse models of PJS. The mesenchymal cells secreted less TGFβ and this correlated with increased proliferation of the epithelial cells. TGFβ has been shown previously to prevent epithelial cell proliferation early in tumorigenesis. These findings support the theory that PJS intestinal polyps might not arise as a result of LKB1 loss in epithelial cells.

Tumorigenesis

Atypical protein kinase C regulates dual pathways for degradation of the oncogenic coactivator SRC-3/AIB1 Yi, P. et al. Mol. Cell 29, 465–476 (2008)

Nuclear receeptor coactivator 3 (NCOA3; also known as SRC-3 and AIB1) is a steroid receptor co-activator that is amplified and overexpressed in a number of cancers, including breast cancer. This papers reports that proteasomal degradation of SRC-3 can be reduced by phosphorylation of carboxyl-terminal residues by atypical protein kinase C (aPKC) in an oestrogen receptor (ER)-dependent manner. Moreover, this increases ER-dependent gene transcription and cell growth. The authors found that aPKC expression levels correlated with SRC-3 levels in several cancer cell lines. Thus, overexpression of aPKC, which occurs in several cancer types, might contribute to tumorigenesis owing to its effects on SRC-3 and ER-dependent gene transcription.

Mechanotransduction

Tumor cell cycle arrest induced by shear stress: roles of integrins and Smad Chang, S.-F. et al. Proc. Natl Acad. Sci. USA 105, 3927–3932 (2008)

Interstitial fluid flow within and surrounding a tissue can affect the mechanical environment, which is characterized by shear stress, pressure forces and tethering force between a cell and the surrounding matrix. These forces are thought to influence proliferation, metastasis, invasion and drug delivery, although the mechanism is unclear. Chang and colleagues found that shear stress induced G2/M cell cycle arrest — which is associated with inhibition of differentiation — in four tumour cell lines, whereas static conditions resulted in G0/G1 arrest. Moreover, they found that the G2/M arrest was mediated by αvβ3 and αvβ1 integrins and that reduction in the binding activity of the downstream transcription factor RUNX2 resulted in downregulation of cell cycle regulatory proteins that lead to G2/M arrest, indicating that these integrins regulate G2/M arrest through RUNX2.