title: Does TGF-β induced formation of actin stress fibres reinforce Smad dependent TGF-β signalling in the prostate?
abstract: In the normal prostate, and during early stages of prostate cancer (PCa) development, the cytokine transforming growth factor beta (TGF-β) acts as a tumour suppressor by inducing cytostasis and apoptosis. However, during tumour development these Smad signalling-dependent endpoints are lost in favour of Smad-independent tumourigenic actions of TGF-β. In this working hypothesis we present an argument for an intimate association between the TGF-β signalling pathway and the actin cytoskeleton that acts to reinforce the tumour suppressive actions of TGF-β in the normal prostate epithelial cell. The rationale is that TGF-β induces expression of the actin binding and stabilising proteins transgelin and tropomyosin. Expression of these proteins is progressively repressed during PCa development, and is inhibited by constitutive activation of the Ras/MEK/ERK pathway, also known to antagonise TGF-β tumour suppression in PCa. The subsequent de-stabilisation of the actin cytoskeleton might, therefore, result in suppression of TGF-β/Smad signalling as an intact link between cytoskeleton and TGF-β receptor/Smad complex is essential. Filamin A is a scaffold protein that provides this link for receptor associated Smads. It is required for activation of the TGF-β signal transduction pathway. Thus, actin filament disorganisation would prevent Filamin A/R-Smad mediated TGF-β signalling, a subsequent loss of tumour suppression and hence promote the progression of PCa. Furthermore, it could be one mechanism by which the switch to a TGF-β tumourigenic response occurs.
authors.affiliation: Physiology, Bosch Institute, School of Medical Sciences, University of Sydney, NSW 2006, Australia. stephen.assinder@sydney.edu.au
authors.forename: Stephen
authors.initials: S
authors.lastname: Assinder
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cole
mesh_terms: D000199:Actins / Q000378:metabolism*; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
chemical_list: D000199:Actins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta