Cell cycle-dependent ciliogenesis and cancer

Abstract

In mammals, most cell types have primary cilia, protruding structures involved in sensing mechanical and chemical signals from the extracellular environment that act as major communication hubs for signaling controlling cell differentiation and polarity. The list of clinical disorders associated with ciliary dysfunction has expanded from polycystic kidney disease to include many others. Transformed cells commonly lack cilia, but whether this lack is cause or consequence of transformation is not well understood. Here we discuss work addressing recently identified actions of the cancer-promoting proteins Aurora A and HEF1/NEDD9/CAS-L at cilia. Together with older studies, this work suggests that loss of cilia in cancer may contribute to the insensitivity of cancer cells to environmental repressive signals, based in part on derangement of cell cycle checkpoints governed by cilia and centrosomes.

Figure 1

A. The cilium as an environmental rheostat: coordination of cancer-related signaling molecules. PDGF-AA binding to the PDGFRαα receptor located at the ciliary membrane induces phosphorylation and activation of the Akt and Mek1/2-Erk1/2 signaling pathways. Sonic hedgehog (Shh) binding to Patched (Ptch) relieves inhibition of the Smoothened protein (Smo), and initiates a signaling cascade that result in activation of the Gli family of zinc-finger transcription factors. Localization of the Smo receptor to primary cilia is important for this signaling cascade. Aberrant Shh signaling was recently observed in a variety of epithelial cancers, and it has been shown that the Shh target Gli1 regulates expression of Snail, a gene important for epithelial-mesenchymal transition (EMT). pVHL and GSK-3β also localize to primary cilia, and act together to maintain the primary cilium: their combined inactivation leads to loss of cilia, and correlates with renal tumor progression. B. Centrosome serves as the signaling molecules hub licensing cell cycle progression. As cells emerge from quiescence and resorb cilia, the CDK2-cyclin E complex progressively associates with the centrosome and triggers the G1/S transition. Centrosome duplication and DNA synthesis are tightly connected through cyclin E/Cdk2 activation. Overexpression of IFT88 prevents G1-S transition, while depletion of IFT88 induces cell cycle progression. The cell cycle checkpoint regulator p53 evaluates centrosome integrity in cell cycle. p53 accumulation at the centrosome is preceded by p38-dependent phosphorylation, and is important for execution of G1/S arrest. Deletion or mutations in p53 gene were found in over 50% of all human cancers: consequences if any for ciliary integrity are not known. C. Model for HEF1– Aurora A – HDAC6 signaling at cilia. Extracellular factors bind to growth factor receptors (GFR) to induce HEF1. HEF1 binds to Aurora A kinase, promoting its activation. Aurora A in turn phosphorylates and activates cilia-associated HDAC6. Moving along the ciliary axomene, HDAC6 deacetylates substrates, causing ciliary resorption. These events occur as an early transient response of G0/G1 cells to serum treatment, as well as at G2/M transition in response to intrinsic signaling cues.