The protein Id: A negative regulator of helix-loop-helix DNA binding proteins

Benezra, Robert; Davis, Robert L.; Lockshon, Daniel; Turner, David L.; Weintraub, Harold

doi:10.1016/0092-8674(90)90214-y

Cited by 2,148 publications

(1,705 citation statements)

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“…Among the 588 genes represented on this filter, only three appeared to be regulated by activin A. One of them encodes Id1, a negative regulator of bHLH transcription factors (Benezra et al, 1990). To verify this regulation and to determine, if other Id family members are also regulated by activin, we treated quiescent human HaCaT keratinocytes with activin A for different time periods.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

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

et al. 2005

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“…The inhibitor of differentiation (Id) or DNA-binding genes were originally identified in murine myoblasts, where they prevented myogenic basic helix-loop-helix transcription factors from binding muscle-specific regulatory elements (Benezra et al, 1990). Over the past several years, Id-1 has been thought to be an oncogene, which is overexpressed in various human cancers.…”

Section: Introductionmentioning

confidence: 99%

Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

et al. 2008

Oncogene

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Inhibitor of differentiation-1 (Id-1) has been accepted as a putative oncogene to promote oncogenic processes through inactivation of tumor suppressors and activation of growth promoting pathways. Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53. Id-1 negatively regulated both p53 and PTEN at the transcriptional level. In promoter assay with serial deletion and chromatin immunoprecipitation assay, the binding of p53 to the PTEN promoter was reduced by Id-1, suggesting that Id-1 regulates PTEN transcription through its p53 modulation. This led to Akt phosphorylation at Ser473 and the activation of the Akt-mediated canonical Wnt signaling pathway. The glycogen synthase kinase-3b phosphorylation at Ser9, stabilization and nuclear localization of b-catenin, T-cell factor (TCF)/lymphoid enhancer factor transactivation activity and cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27 Kip1 phosphorylation at Thr157 and its cytosolic localization were also increased in Id-1 overexpressing MCF7 cells. In conclusion, our results disclose Id-1 as a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27 Kip1 phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.

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“…ID proteins form DNA-binding incompetent heterodimers with bHLH transcription factors thereby inhibiting their transcriptional activities (Benezra et al, 1990). Individual ID-proteins have been linked to inhibiting cellular differentiation, inhibition of bHLHand other transcription factors (Benezra et al, 1990;Jen et al, 1992;Kreider et al, 1992;Ohtani et al, 2001;Roberts et al, 2001), modulating apoptosis (Florio et al, 1998;Ling et al, 2003), cooperating with the retinoblastoma tumor suppressor pathway (Iavarone et al, 1994;Hara et al, 1996), extending cellular life span (Alani et al, 1999;Nickoloff et al, 2000;Tang et al, 2002), regulating angiogenesis (Lyden et al, 2001) as well as cardiac development (Fraidenraich et al, 2004), and stem cell maintenance (Ying et al, 2003). ID expression is induced as part of the immediate-early transcriptional response to growth factors and is regulated in a cell cycle-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Interference of the dominant negative helix–loop–helix protein ID1 with the proteasomal subunit S5A causes centrosomal abnormalities

2007

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The inhibitor of DNA-binding (ID) proteins are dominantnegative inhibitors of basic helix-loop-helix transcription factors that have multiple functions during development and cellular differentiation. High-level expression of some ID family members has been observed in human malignancies, and in some cases was correlated with poor clinical prognosis. Ectopic ID1 expression extends the life span of primary human epithelial cells, inhibits cellular differentiation and induces centrosome duplication errors, thus suggesting that ID1 may have oncogenic activities. ID1 can bind to the proteasomal subunit S5A/Rpn10, but the biological consequences of the interaction have not been studied in detail. Here, we show that ID1's ability to induce supernumerary centrosomes correlates with S5A binding. Similar to ID1, a fraction of the S5A protein localizes to centrosomal structures. Furthermore, partial depletion of S5A by RNA interference causes accumulation of cells with supernumerary centrosomes. These results are consistent with the model that ID1 dysregulates centrosome homeostasis at least in part by interfering with S5A activities at the centrosome.

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The protein Id: A negative regulator of helix-loop-helix DNA binding proteins

Cited by 2,148 publications

References 47 publications

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

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

Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

Interference of the dominant negative helix–loop–helix protein ID1 with the proteasomal subunit S5A causes centrosomal abnormalities

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