Tumor suppressor genes in the tumor microenvironment.

Tumor suppressor genes (TSGs) are thought to suppress tumor development primarily via cancer cell-autonomous mechanisms. However, the tumor microenvironment (TME) also significantly influences tumorigenesis. In this context, a role for TSGs in the various cell types of the TME in regulating tumor growth is emerging.

JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1.

The c-Jun-NH2-terminal kinases (JNKs) regulate cell death, generally through the direct phosphorylation of both pro- and anti-apoptotic substrates. In this report, we demonstrate an alternate mechanism of JNK-mediated cell death involving the anti-apoptotic protein human apurinic/apyrimidinic endonuclease 1 (APE1). Treatment of cells with a variety of genotoxic stresses enhanced APE1-JNK (all isoforms of JNK1 or JNK2) interaction, specifically in cells undergoing apoptosis.

PAK5 is auto-activated by a central domain that promotes kinase oligomerization.

PAKs (p21 activated kinases) are an important class of Rho effectors. These contain a Cdc42-Rac1 interaction and binding (CRIB) domain and a flanking auto-inhibitory domain (AID) which binds the C-terminal catalytic domain. The group II kinases PAK4 and PAK5 are considered significant therapeutic targets in cancer.