title: Differentiation-associated reprogramming of the transforming growth factor β receptor pathway establishes the circuitry for epithelial autocrine/paracrine repair.
abstract: Transforming growth factor (TGF) β has diverse and sometimes paradoxical effects on cell proliferation and differentiation, presumably reflecting a fundamental but incompletely-understood role in regulating tissue homeostasis. It is generally considered that downstream activity is modulated at the ligand:receptor axis, but microarray analysis of proliferative versus differentiating normal human bladder epithelial cell cultures identified unexpected transcriptional changes in key components of the canonical TGFβ R/activin signalling pathway associated with cytodifferentiation. Changes included upregulation of the transcriptional modulator SMAD3 and downregulation of inhibitory modulators SMURF2 and SMAD7. Functional analysis of the signalling pathway revealed that non-differentiated normal human urothelial cells responded in paracrine mode to TGFβ by growth inhibition, and that exogenous TGFβ inhibited rather than promoted differentiation. By contrast, in differentiated cell cultures, SMAD3 was activated upon scratch-wounding and was involved in promoting tissue repair. Exogenous TGFβ enhanced the repair and resulted in hyperplastic scarring, indicating a feedback loop implicit in an autocrine pathway. Thus, the machinery for autocrine activation of the SMAD3-mediated TGFβR pathway is established during urothelial differentiation, but signalling occurs only in response to a trigger, such as wounding. Our study demonstrates that the circuitry of the TGFβR pathway is defined transcriptionally within a tissue-specific differentiation programme. The findings provide evidence for re-evaluating the role of TGFβR signalling in epithelial homeostasis as an autocrine-regulated pathway that suppresses differentiation and promotes tissue repair. This provides a new paradigm to help unravel the apparently diverse and paradoxical effect of TGFβ signalling on cell proliferation and differentiation.
authors.affiliation: Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, University of York, York, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Fleming
authors.forename: Saqib
authors.initials: S
authors.lastname: Shabir
authors.forename: Claire L
authors.initials: CL
authors.lastname: Varley
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kirkwood
authors.forename: Angela
authors.initials: A
authors.lastname: White
authors.forename: Julie
authors.initials: J
authors.lastname: Holder
authors.forename: Ludwik K
authors.initials: LK
authors.lastname: Trejdosiewicz
authors.forename: Jennifer
authors.initials: J
authors.lastname: Southgate
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D019899:Paracrine Communication / Q000187:drug effects; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D019459:Urothelium / Q000166:cytology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta