Id2 Mediates Tumor Initiation, Proliferation, and Angiogenesis in <i>Rb</i> Mutant Mice

Lasorella, Anna; Rothschild, Gerson; Yokota, Yoshifumi; Russell, Robert G.; Iavarone, Antonio

doi:10.1128/mcb.25.9.3563-3574.2005

Cited by 102 publications

(94 citation statements)

References 65 publications

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“…Among other members, Id2 was found to play a crucial role in the regulation of differentiation, cell cycle and proliferation in epithelial cells. It acts as a dominant negative antagonist of Rb and abrogates the tumor suppressor function of Rb, thereby promoting entry into S phase and cell proliferation (Lasorella et al, 2001(Lasorella et al, , 2005.…”

Section: Discussionmentioning

confidence: 99%

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

et al. 2007

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We investigated the effect of all-trans-retinoic acid (atRA) on proliferation in several human skin cell lines and found that antiproliferative potency of atRA correlated with the endogenous activity of canonical Wnt signaling. In HaCaT keratinocytes, we found that atRA significantly suppressed the expression of Id2, a member of the inhibitor of differentiation family of transcription factors that regulate cell growth and differentiation. However, no apparent change in the expression of other Wnt targets, like c-Myc or cyclin D1, was observed. Retinoid-induced Id2 gene suppression was associated with decreased levels of histone H3 and H4 acetylation and histone H3 Lys-4 methylation, and with recruitment of the LSD1 demethylase at the Wnt-response element (WRE) (TCF/LEF-binding site), in the Id2 gene promoter. None of such changes was detected at the WRE of c-Myc and cyclin D1 gene promoters. Inhibition of Id2 by short interfering RNA (siRNA) had a similar effect on the proliferation of HaCaT cells as exposure to atRA, whereas anti-b-catenin siRNA significantly inhibited its antiproliferative effect. These data suggest that downregulation of Id2 gene expression through transcriptional convergence between Wnt and retinoid signaling pathways underlies the antiproliferative effect of retinoids in keratinocytes, and provide evidence of gene-targeted crosstalk between signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

et al. 2007

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“…Although Rb has no effect on PU.1-binding alone, it is able to reverse Id2 repression. An additional genetic interaction has been shown in tumor suppression: Rb þ /À;Id2À/À pituitary glands show decreased proliferation, premature differentiation, and decreased pituitary tumor incidence relative to Rb þ /À glands, presumably due to loss of Id2's inhibitory effect on transcription factors involved in differentiation (Lasorella et al, 2005). However, this observed effect may not reflect a direct physical interaction between Rb and Id2 since these two proteins may control different events in pituitary development.…”

Section: Studies Of Rb Family Proteins In Micementioning

confidence: 99%

Retinoblastoma family genes

2006

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“…Aberrant elevation of Id2, typically activated by oncoproteins such as Myc and Ews-Fli1, was frequently observed in tumors from the central and peripheral nervous system (9)(10)(11)(12). The aberrant accumulation of Id2 contributes to uncontrolled proliferation and neoangiogenesis, two hallmarks of neural cancers (13).…”

Section: Introductionmentioning

confidence: 99%

FHL2 interacts with and acts as a functional repressor of Id2 in human neuroblastoma cells

Han

Zhao

et al. 2009

Chin. J. Cancer Res.

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Inhibitor of differentiation 2 (Id2) is a natural inhibitor of the basic helix-loop-helix transcription factors. Although Id2 is well known to prevent differentiation and promote cell-cycle progression and tumorigenesis, the molecular events that regulate Id2 activity remain to be investigated. Here, we identified that Four-and-a-half LIM-only protein 2 (FHL2) is a novel functional repressor of Id2. Moreover, we demonstrated that FHL2 can directly interact with all members of the Id family (Id1-4) via an N-terminal loop-helix structure conserved in Id proteins. FHL2 antagonizes the inhibitory effect of Id proteins on basic helix-loop-helix protein E47-mediated transcription, which was abrogated by the deletion mutation of Ids that disrupted their interaction with FHL2. We also showed a competitive nature between FHL2 and E47 for binding Id2, whereby FHL2 prevents the formation of the Id2-E47 heterodimer, thus releasing E47 to DNA and restoring its transcriptional activity. FHL2 expression was remarkably up-regulated during retinoic acidinduced differentiation of neuroblastoma cells, during which the expression of Id2 was opposite to that. Ectopic FHL2 expression in neuroblastoma cells markedly reduces the transcriptional and cell-cycle promoting functions of Id2. Altogether, these results indicate that FHL2 is an important repressor of the oncogenic activity of Id2 in neuroblastoma cells.

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Id2 Mediates Tumor Initiation, Proliferation, and Angiogenesis in Rb Mutant Mice

Cited by 102 publications

References 65 publications

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

Retinoblastoma family genes

FHL2 interacts with and acts as a functional repressor of Id2 in human neuroblastoma cells

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