Mad Upregulation and Id2 Repression Accompany Transforming Growth Factor (TGF)-β-mediated Epithelial Cell Growth Suppression

Siegel, Peter M.; Shu, Weiqun; Massagué, Joan

doi:10.1074/jbc.m301413200

Cited by 90 publications

(58 citation statements)

References 53 publications

(61 reference statements)

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“…25,26 More recently, it has been shown that Id2 expression is dependent on myc-max transcriptional complexes in HaCaT and NMuMG cells. 27 In contrast to Id1 and Id2, the molecular mechanism by which TGF-b regulates the expression of Id3 is still unclear. In B-lymphocyte cells, stimulation by TGF-b for 1 h increased the expression of Id3 mRNA, and Id2 was also upregulated by TGF-b.…”

Section: Discussionmentioning

confidence: 99%

A role for Id in the regulation of TGF-β-induced epithelial–mesenchymal transdifferentiation

et al. 2004

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Epithelial-mesenchymal transdifferentiation (EMT) is a critical morphogenic event that occurs during embryonic development and during the progression of various epithelial tumors. EMT can be induced by transforming growth factor (TGF)-b in mouse NMuMG mammary epithelial cells. Here, we demonstrate a central role of helix-loop-helix factors, E2A and inhibitor of differentiation (Id) proteins, in TGF-b-induced EMT. Epithelial cells ectopically expressing E2A adopt a fibroblastic phenotype and acquire migratory/invasive properties, concomitant with the suppression of E-cadherin expression. Id proteins interacted with E2A proteins and antagonized E2A-dependent suppression of the E-cadherin promoter. Levels of Id proteins were dramatically decreased by TGF-b. Moreover, NMuMG cells overexpressed Id2 showed partial resistance to TGF-b-induced EMT. Id proteins thus inhibit the action of E2A proteins on the expression of E-cadherin, but after TGF-b stimulation, E2A proteins are present in molar excess of the Id proteins, thus over-riding their inhibitory function and leading to EMT.

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Section: Discussionmentioning

confidence: 99%

A role for Id in the regulation of TGF-β-induced epithelial–mesenchymal transdifferentiation

et al. 2004

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“…Tieg2b͞Tieg3 is a TGF␤-inducible transcriptional repressor with antiproliferative and antiapoptotic functions (35). Idb2 encodes Id2 (inhibitor of differentiation), which is also involved in transcriptional inhibitory responses to TGF␤ (36)(37)(38) in cell growth control and angiogenesis (36,37,39,40). Other genes involved in cell proliferation include Ornithine decarboxylase (Odc) and Ribonucleotide reductase 2 (Rrm2), and those involved in modifying cellular plasticity and migration encode Rho kinase (Rock2), integrin ␤1-binding protein 1 (Itgb1bp1͞ LCAP1), and TNF␣-converting enzyme (Adam17).…”

Section: Discussionmentioning

confidence: 99%

Genetic variants ofTgfb1act as context-dependent modifiers of mouse skin tumor susceptibility

Mao¹,

Saunier²,

Koning³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The human TGFB1 gene is polymorphic, and genetic variants are associated with altered cancer risk. However, human genetic association studies have had variable outcomes because TGF␤1 action is context-dependent. We used the murine skin model of chemical carcinogenesis in genetic linkage analysis of three independent Mus musculus NIH͞Ola ؋ (Mus spretus ؋ M. musculus NIH͞Ola)F 1 backcrosses, to identify a skin tumor susceptibility locus, Skts14, on proximal chromosome 7. Tgfb1 maps at the peak of linkage. The mouse Tgfb1 gene is polymorphic, resulting in cis-regulated differential allelic mRNA expression between M. spretus and M. musculus in F 1 mouse skin. This phenomenon is reflected in differential phospho-SMAD2 levels, downstream of TGF␤ signaling, between these two mouse species. In normal F1 mouse skin, the Tgfb1 SPR allele is expressed at higher levels than the Tgfb1 NIH allele, and this differential is accentuated by phorbol 12-myristate 13-acetate treatment. In benign F1 papillomas, this imbalance is reversed, possibly by selection against expression of a hyperactive Tgfb1 SPR allele in TGF␤ growth-responsive tumors. We demonstrate that skin tumor susceptibility is altered by Tgfb1 gene dosage, but that manifestation of Tgfb1-linked skin tumor susceptibility in M. musculus NIH͞Ola ؋ (M. spretus ؋ M. musculus NIH͞Ola)F1 backcross mice depends on interactions with another unlinked tumor modifying locus, Skts15, that overlaps Tgfbm3 on chromosome 12. These findings illustrate the power of complex genetic interactions in determining disease outcome and have major implications to the assessment of disease risk in individuals harboring variant TGFB1 alleles.carcinoma ͉ chemical skin carcinogenesis ͉ genetic interaction ͉ TGF␤

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“…Thus, in addition to TGF-b (Ling et al, 2002;Kretschmer et al, 2003;Siegel et al, 2003;Kowanetz et al, 2004), activin was identified as a novel regulator of Id gene expression. Similar to TGF-b, activin has opposite effects on keratinocytes and fibroblasts.…”

Section: Id Proteins In Epidermal Homeostasismentioning

confidence: 99%

Id proteins: Novel targets of activin action, which regulate epidermal homeostasis

et al. 2005

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Activin is a member of the transforming growth factor b (TGF-b) family, which plays a crucial role in skin morphogenesis and wound healing. To gain insight into the underlying mechanisms of action, we searched for activin-regulated genes in cultured keratinocytes. One of the identified target genes encodes Id1, a negative regulator of helix-loop-helix transcription factors. We show that Id1, Id2, and Id3 are strongly downregulated by activin in keratinocytes in vitro and in vivo. To determine the role of Id1 in keratinocyte biology, we generated stable HaCaT keratinocyte cell lines overexpressing this protein. Our results revealed that enhanced levels of Id1 do not affect proliferation of keratinocytes in monoculture under exponential culture conditions or in response to activin or TGF-b1. However, in three-dimensional organotypic cultures, Id1-overexpressing HaCaT cells formed a hyperthickened and disorganized epithelium that was characterized by enhanced keratinocyte proliferation, abnormal differentiation, and an increased rate of apoptosis. These results identify an important function of Id1 in the regulation of epidermal homeostasis.

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Mad Upregulation and Id2 Repression Accompany Transforming Growth Factor (TGF)-β-mediated Epithelial Cell Growth Suppression

Cited by 90 publications

References 53 publications

A role for Id in the regulation of TGF-β-induced epithelial–mesenchymal transdifferentiation

A role for Id in the regulation of TGF-β-induced epithelial–mesenchymal transdifferentiation

Genetic variants ofTgfb1act as context-dependent modifiers of mouse skin tumor susceptibility

Id proteins: Novel targets of activin action, which regulate epidermal homeostasis

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