Genealogy, expression, and cellular function of transforming growth factor-β

doi:10.1016/S0163-7258(03)00035-4

Pharmacology & Therapeutics

Volume 98, Issue 2, May 2003, Pages 257-265

https://doi.org/10.1016/S0163-7258(03)00035-4 Get rights and content

Abstract

The transforming growth factor-β (TGF-β) gene superfamily expresses a large set of structurally and functionally related polypeptides. Three TGF-β isoforms are regulated by specific genes and have been identified in mammals (TGF-β1, -β2, and -β3). All three-protein isoforms are observed abundantly during development and display overlapping and distinct spatial and temporal patterns of expressions. Each isoform plays a distinct role, the nature of which depends on the cell type, its state of differentiation, and growth conditions, and on the other growth factors present. TGF-β regulates many of the processes common to both tissue repair and disease, including angiogenesis, chemotoxins, fibroblast proliferation and the controlled synthesis, and degradation of matrix proteins, such as collagen and fibronectin. This review will examine the genealogy and mode of actions of TGF-β on the cell types involved in inflammation and repair, as well as in carcinoma.

Introduction

Transforming growth factor-β (TGF-β) was first characterised after purification from human placenta in 1983 (Frolik et al., 1983), and human platelets were recognized as containing large amounts of the peptides Assoian et al., 1983, Assoian et al., 1984. TGF-β1 is the prototype of its highly homologous isoforms TGF-β2 and -β3, as well as a superfamily of over 40 different related proteins, presumed to have derived from a common ancestor gene Kingsley, 1994, Roberts & Speared, 1990. TGF-β1 appears to play the major role, both quantitatively and qualitatively. Biological actions of TGF-β in vitro are very diverse. It has been shown to stimulate cellular proliferation in vitro, but is generally considered to be an inhibitor of proliferation and a promoter of cellular hypertrophy and differentiation Choi et al., 1993, Roberts & Speared, 1990. TGF-β has also been shown to block or initiate cellular differentiation and cell migration, depending upon the cell type and culture conditions (Roberts & Speared, 1990). The inhibitory action is quite broad, targeting epithelial, endothelial, and haemopoeitic cells.

Section snippets

Transcriptional regulation of transforming growth factor-β

The three mammalian isoforms are regulated at the transcriptional level. The promoters (Roberts, 1998) for TGF-β2 and -β3 each contain TATAA boxes and a common proximal CRE-ATF site, which suggests that these promoters are subject to hormonal and developmental control Lafyatis et al., 1990, O'Reilly et al., 1992. The promoter for TGF-β1 lacks the classic TATAA box, but has multiple regulatory sites that can be activated by immediate early genes, such as c-jun, c-fos, and egr-1, by a number of

Transforming growth factor-β and receptors

There are currently five distinct isoforms of TGF-β with 64–82% identity, with only the TGF-β1, -β2, and -β3 forms expressed in mammalian tissues. In humans, the three isoforms are located on three different chromosomes, 19q13, 1q41, and 14q24, respectively (Roberts, 1998).

Members of the TGF-β superfamily signal through a family of transmembrane receptor-linked serine/threonine kinases that all have a characteristic structure that includes a short cysteine-rich extracellular domain, a single

Signalling

Biologic signals for TGF-β are transduced through heteromeric complexes of two transmembrane serine/threonine kinase receptors Attisano & Wrana, 2000, Heldin et al., 1997, Massague, 1998. These receptors act in concert to activate signalling (Fig. 1). Upon binding to TGF-β, the TβRII receptor forms a heteromeric complex with the TβRI receptor, resulting in the phosphorylation and activation of the TβRI (Wrana et al., 1994). The activated TβRI then interacts with an adaptor protein Smad anchor

Angiogenesis

It is generally thought that TGF-β1 plays an important role in vascular remodelling Pepper, 1997, Risau, 1997. TGF-β1 can inhibit the activities of other angiogenic factors in endothelial proliferation and migration under most cell culture conditions and can simulate the production of extracellular matrix proteins and proteinase inhibitors (Pepper, 1997). However, TGF-β1 displays a biphasic effect on angiogenesis. Low concentrations of TGF-β1 synergistically enhance, whereas high concentrations

Inflammation and repair

TGF-β has been considered a candidate for gene therapy of orthopaedic diseases. Lee et al. (2001) injected fibroblasts expressing active TGF-β1 into the knee joints of rabbits with artificial cartilage defects. At 2–3 weeks after injection, there was evidence of cartilage regeneration, and at 4–6 weeks, the cartilage defect was completely filled with newly grown hyaline cartilage. Inflammatory bowel disease is a chronic inflammation of the gastrointestinal tract. Deficiency of TGF-β signalling

Cancer

Most carcinomas are characterised by a loss of normal growth-inhibitory and apoptotic responses to TGF-β (Reiss, 1997). This loss of responsiveness is typically the result of loss of TGF-β receptor expression or defects in downstream signalling events controlled by TGF-β Hoodless & Wrana, 1998, Massague, 1998. In a subset of colon and pancreatic tumours, this is caused by inactivating defects of TGF-β receptors and Smad4/DPC4, but the majority of tumours with loss of growth inhibition do not

Conclusion

The TGF-β superfamily of growth factors regulates a diverse number of biological processes. While we currently have a fairly good understanding of their molecular and cellular biology, their signalling pathways and mechanisms that mediate their effects on target cells are only beginning to be deciphered. An understanding of the mechanisms of activation of LTGFβ will be essential in order to define more completely its regulation and role in health and disease. This knowledge will enable the

Acknowledgements

Research grant support from the Medical Research Council (MRC, SA), National Research Foundation (NRF, SA), and Durban Institute of Technology is much appreciated.

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Genealogy, expression, and cellular function of transforming growth factor-β

Abstract

Introduction

Section snippets

Transcriptional regulation of transforming growth factor-β

Transforming growth factor-β and receptors

Signalling

Angiogenesis

Inflammation and repair

Cancer

Conclusion

Acknowledgements

J. Urol.

J. Biol. Chem.

Cytokine Growth Factor Rev.

Curr. Opin. Cell Biol.

Cell

Biochim. Biophys. Acta

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Kidney Int.

Cell

J. Biol. Chem.

Cell

Cell

J. Biol. Chem.

Mol. Med. Today

J. Biol. Chem.

Mutat. Res.

J. Biol. Chem.

Am. J. Pathol.

Kidney Int.

J. Biol. Chem.

Curr. Biol.

J. Biol. Chem.

Cytokine Growth Factor Rev.

Exp. Cell Res.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Cell

Biochem. Biophys Res Commun.

Biol. Chem.

Transforming growth factor β1 inhibits mouse keratinocytes late in G1 independent of effects on gene transcription

Cancer Res.

Cellular transformation by coordinated action of three peptide growth factors from human platelets

Nature

TGF β I prostate cancer: a growth inhibitor that can enhance tumorigenicity

Prostate

Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex

Mol. Cell Biol.

A transcriptional partner for Mad proteins in TGF-beta signalling

Nature (London)

Genomic analysis of metastasis reveals an essential role for RhoC

Nature (London)

Effect of healing on the expression of transforming growth factor beta(s) and their receptors in chromic venous leg ulcers

J. Physiol.

Direct binding of Smad3 and Smad4 to critical TGF β-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene

EMBO J.

Human transforming growth factor-b cDNA sequence and expression in tumor cell lines

Nature (London)

Repression of the transforming growth factor-β1 gene by the Wilm's tumour suppressor WT1 gene product

Mol. Endocrinol.

Mechanisms of transforming growth factor-β receptor endocytosis and intracellular sorting differ between fibroblasts and epithelial cells

Mol. Biol. Cell

Purification and initial characterisation of a type beta transforming growth factor from human placenta

Proc. Natl. Acad. Sci. USA

Basic fibroblast growth factor and transforming growth factor beta-1: synergistic mediators of angiogenesis in vitro

J. Cell Physiol.

Transforming growth factor β receptor signalling and endocytosis are linked through a COOH terminal activation motif in the type I receptor

Mol. Biol. Cell

Loss of expression of transforming growth factor-beta type II receptor correlates with high tumour grade in human breast in situ and invasive carcinomas

Histopathology

Mutation of the type II transforming growth factor beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas

Cancer Res.

The latent transforming growth factor β-binding protein-1 promotes in vitro differentiation of embryonic stem cells into endothelium

Mol. Biol. Cell

Hereditary haemorrhagic telangiectasia

N. Engl. J. Med.

Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease