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

Abstract

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.

TGF-β Induces Growth Arrest in Burkitt Lymphoma Cells via Transcriptional Repression of E2F-1

“…TGF-␤ has been observed to repress expression of the Id transcription factors in epithelial cells (32). In contrast, we found that TGF-␤ treatment of CA46 BL cells readily induced expression of Id1 and Id2, indicating that this may be an example of cell type differences in the TGF-␤ response.…”

Gain of 11q/cyclin D1 overexpression is an essential early step in skin cancer development and causes abnormal tissue organization and differentiation

“…Although all HaCaT-cyclin clones were still able to stratify, detailed analysis of the differentiation process demonstrated deregulation of the well-ordered sequential expression particularly of the late differentiation markers. This phenotype was unexpected because it was observed neither in vectortransfected control cells used in this or previous studies nor after transfection with other oncogenes including Ha-ras or c-myc (Boukamp et al, 1990;Cerezo et al, 2003;Rotzer et al, 2006). This strongly excludes clonal variation of the HaCaT population as being causal for this phenotype, but suggests a very specific and novel role of cyclin D1 in this process.…”

Large Scale RNAi Screen Reveals That the Inhibitor of DNA Binding 2 (ID2) Protein Is Repressed by p53 Family Member p63 and Functions in Human Keratinocyte Differentiation

“…Furthermore, p63 is crucial for the activation of the epithelial cell adhesion program (47) or to maintain the proliferative potential of stem cells (48). Taking into account the well-established roles of ID2 in controlling epidermal homeostasis and cell fate in human keratinocytes (13)(14)(15)(16), including its capacity to inhibit differentiation (6,32,49) the regulatory link that we observe between p63 and ID2 seems particularly interesting. Indeed, as it was recently suggested in an excellent review on epidermal homeostasis (50) that the identification of key genes downstream of p63 would provide important new insights into its roles in dynamic equilibrium of differentiation and proliferation.…”

“…The anti-proliferative effect of retinoids on human keratinocytes seems to result from the down-regulation of ID2 gene expression through a transcriptional convergence between Wnt and retinoid signaling (14). Transforming growth factor ␤ (TGF␤) also inhibits growth of epithelial cells, including keratinocytes, through long term repression of ID2 and ID3 (15,16). Similarly ID2 promotes tumor cell proliferation via control of cyclin D1 protein level (17).…”

“…Similarly ID2 promotes tumor cell proliferation via control of cyclin D1 protein level (17). Finally, small enhancement of ID1 expression, but likely of other ID proteins as well, affects proliferation, differentiation, and apoptosis of keratinocytes grown in organotypic cultures (16).…”