Mechanisms of TGF-β signaling in regulation of cell growth and differentiation

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Abstract

Transforming growth factor β (TGF-β) is a secreted protein that regulates proliferation, differentiation and death of various cell types. All immune cell lineages, including B, T and dendritic cells as well as macrophages, secrete TGF-β, which negatively regulates their proliferation, differentiation and activation by other cytokines. Thus, TGF-β is a potent immunosuppressor and perturbation of TGF-β signaling is linked to autoimmunity, inflammation and cancer. Regulation of cell proliferation and differentiation by TGF-β is a topic of great basic and clinical importance. We summarize our work on the growth inhibitory pathway downstream of TGF-β, which is triggered by receptor serine/threonine kinases at the cell surface and downstream effectors of the Smad family. Activated Smads regulate transcription of target genes, including cell cycle inhibitors such as p21, which mediate the anti-proliferative response and partially explain the tumor suppressive action of the TGF-β pathway. We have described a molecular mechanism of regulation of the p21 gene by Smads and transcription factor Sp1. At late stages of tumor progression, TGF-β promotes tumorigenesis via suppression of the immune system and changes in cell differentiation of epithelial tumor cells, a phenomenon termed epithelial to mesenchymal transdifferentiation (EMT). We review our work on the role of the Smad pathway in controling EMT. In conclusion, the molecular pathways that describe the anti-proliferative and transdifferentiating effects of TGF-β in epithelial cells have been uncovered to great molecular detail; a future challenge will be to test their generality in other systems, including the immune system.

Introduction

Transforming growth factor β (TGF-β) is the prototype of a large superfamily of secreted signaling polypeptides with diverse functions in development and adult tissue homeostasis of all metazoans [1], [2]. At the cellular level, TGF-β inhibits proliferation of epithelial, endothelial and haematopoietic cells, regulates the differentiation of immune, neuronal, mesenchymal and epithelial cell types and modulates their apoptotic response [3], [4], [5]. The physiological effects of TGF-β are manifested in a cell- and context-dependent manner and this cytokine is known for its antithetic action in cells of different developmental lineages [6].

TGF-β signals via receptor serine/threonine kinases, termed type I and type II receptors, that form complexes with the ligand on the cell surface resulting in activation of the dormant kinase activity of the type I receptor [7]. This receptor then phosphorylates and activates members of the Smad family of tumor suppressors, termed R-Smads, which includes Smad2 and Smad3 in the case of TGF-β [7], [8]. The activated R-Smads form oligomers with the unique co-Smad, Smad4, and rapidly translocate to the nucleus to regulate expression of target genes. Thus, Smads transiently signal in the nucleus by controling the expression of specific genes whose action will manifest the mutifunctional physiology of TGF-β.

Here, we review one central aspect of the TGF-β action in the immune system, namely the negative control of immune cell proliferation and differentiation. Then, we present our current advances in understanding the growth inhibitory and cell differentiation pathways in epithelial cells, as a framework for future discoveries on the regulation of immune cell function with therapeutic potential.

Section snippets

A central theme in immune cell regulation by TGF-β

TGF-β suppresses growth and differentiation of most immune cell lineages including B and T cells [9]. TGF-β is produced by all such immune cell lineages and acts in an autocrine and paracrine manner. In addition to regulation of immune cell proliferation, TGF-β regulates the expression of cell adhesion and extracellular matrix proteins, especially in the bone marrow and thymic microenvironments. It also acts as a chemoattractant for monocytes/macrophages and inhibits immune cell activation by

Dual role of TGF-β in tumorigenesis

The fact that TGF-β primarily inhibits the proliferation of many cell types, attributes to this cytokine and its signaling pathway a tumor suppressor role [23], [24], [25]. Accordingly, during tumor progression, cancer cells tend to acquire increasing resistance to the growth inhibitory response of TGF-β, e.g. through mutations or inhibition of components along the TGF-β signaling pathway. On the other hand, in most tumors, cancer cells start secreting non-physiological levels of TGF-β which

Regulation of the cell cycle inhibitor p21

We have contributed extensively to the analysis of the growth inhibitory response to TGF-β with respect to the mechanism of activation of the gene for the CKI p21 [44], [45], [46]. We first established firmly that the Smad pathway downstream of the TGF-β receptors is indeed responsible for the upregulation of the p21 gene and its promoter [44], [46]. This was important, as alternative models of regulation of this gene by signaling pathways, such as the mitogen activated protein kinase (MAPK)

Signaling pathways controling epithelial to mesenchymal transdifferentiation

As described above, a second and equally important function of TGF-β during tumorigenesis is its ability to enhance tumor cell invasion and metastasis at late stages of disease progression. Despite the discovery 6 years ago, that TGF-β can act as a factor promoting EMT, only recently has this important physiological effect of TGF-β received proper attention [3], [27], [41]. Through a detailed analysis of ligand-binding specificity, receptor immunoprecipitation and pathway-sensitive gene

Future perspectives and significance to immunology

Here we attempted to summarize an important and central theme of TGF-β biology, the pathways that regulate cell growth and relate to the development of cancer in response to this cytokine. A major conclusion so far is that the primary signaling pathway downstream the TGF-β receptors, namely the Smad pathway, is involved in both the growth inhibitory and pro-tumorigenic or EMT response of epithelial cells. This suggests that these cellular actions of TGF-β need to be explained by specific

Acknowledgments

We would like to acknowledge the essential contribution of Dr D. Kardassis, Dr A. Kurisaki, Dr K. Miyazono, Dr A. Morén, Dr E. Piek, Dr K. Shiraishi, Dr T. Sjöblom and Dr P. ten Dijke to our previous and ongoing research work summarized in this article. The research of our group is funded by the Ludwig Institute for Cancer Research and a grant from the Human Frontier Science Program.

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