Id2 protein is selectively upregulated by UVB in primary, but not in immortalized human keratinocytes and inhibits differentiation

Simbulan-Rosenthal, Cynthia M.; Trabosh, Valerie A.; Velarde, A.; Chou, Feng-Pai; Daher, Ahmad; Tenzin, Fnu; Tokino, Takashi; Rosenthal, Dean S.

doi:10.1038/sj.onc.1208709

Cited by 18 publications

(23 citation statements)

References 85 publications

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“…Our data are in agreement with recent reports that Id2 abrogates girradiation-induced cell-cycle arrest in human keratinocytes (Baghdoyan et al, 2005), and that upregulation of Id2 by UVB stimulates proliferation and predisposes keratinocytes to carcinogenesis by preventing their normal differentiation program (Simbulan-Rosenthal et al, 2005). Significantly, among potential target genes, crosstalk affects expression of only some (such as Id2 or, to a lesser degree, CD44), but not other (such as cyclinD1, c-Myc or EGFR) genes.…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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

et al. 2007

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“…This finding is consistent with other work showing that Id2 is down-regulated in melanomas of the skin and eye (7,43) and that Id2 is capable of inhibiting epithelial differentiation in neural crest (25) and in keratinocytes (44). Our experiments predict the existence of an activator associated with the E-box2 element of the E-cadherin promoter that is inhibited by Id2.…”

Section: Discussionsupporting

confidence: 82%

Functional Gene Expression Analysis Uncovers Phenotypic Switch in Aggressive Uveal Melanomas

et al. 2006

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Microarray gene expression profiling is a powerful tool for generating molecular cancer classifications. However, elucidating biological insights from these large data sets has been challenging. Previously, we identified a gene expression-based classification of primary uveal melanomas that accurately predicts metastatic death. Class 1 tumors have a low risk and class 2 tumors a high risk for metastatic death. Here, we used genes that discriminate these tumor classes to identify biological correlates of the aggressive class 2 signature. A search for Gene Ontology categories enriched in our classdiscriminating gene list revealed a global down-regulation of neural crest and melanocyte-specific genes and an upregulation of epithelial genes in class 2 tumors. Correspondingly, class 2 tumors exhibited epithelial features, such as polygonal cell morphology, up-regulation of the epithelial adhesion molecule E-cadherin, colocalization of E-cadherin and B-catenin to the plasma membrane, and formation of cell-cell adhesions and acinar structures. One of our top class-discriminating genes was the helix-loop-helix inhibitor ID2, which was strongly down-regulated in class 2 tumors. The class 2 phenotype could be recapitulated by eliminating Id2 in cultured class 1 human uveal melanoma cells and in a mouse ocular melanoma model. Id2 seemed to suppress the epithelial-like class 2 phenotype by inhibiting an activator of the E-cadherin promoter. Consequently, Id2 loss triggered up-regulation of E-cadherin, which in turn promoted anchorage-independent cell growth, a likely antecedent to metastasis. These findings reveal new roles for Id2 and E-cadherin in uveal melanoma progression, and they identify potential targets for therapeutic intervention.

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“…DNA microarray analysis revealed that whereas UVB induced a downregulation of Id1 in both cell types, expression of Id2 was upregulated by 10-to 19-fold in primary KC, but not in immortalized cells. On the other hand, expression of Id3 was upregulated fivefold in the immortalized cells (Simbulan-Rosenthal et al, 2005). Consistent with these results, the increased expression of Id3 in immortalized cells, but not in primary KC, was confirmed by RT-PCR analysis ( Figure 1a) and at the protein level after immunoblot analysis (Figure 1b).…”

Section: Uvb Upregulates Id3 Expression In Hpv16supporting

confidence: 83%

“…Three of the four known human inhibitors of differentiation and DNA binding (Id) genes , a class of helix-loop-helix (HLH) transcriptional repressors involved in differentiation, proliferation, apoptosis, and carcinogenesis were found to exhibit significant changes in expression following UVB exposure. Whereas Id1 was downregulated in both primary and immortalized cells upon UVB exposure, Id2 was only upregulated in primary KC, while Id3 was only upregulated in immortalized KC (Simbulan-Rosenthal et al, 2005). We subsequently found that ectopic expression of Id2 in primary KC suppressed differentiation, similar to the effects of UVB, and that Id2 small interfering RNA (siRNA) blocked this UVB response, suggesting that UVB suppresses differentiation of primary KC at least in part via upregulation of Id2 (Simbulan-Rosenthal et al, 2005).…”

Section: Introductionmentioning

confidence: 90%

“…To determine the proximal signals leading to the preferential death of immortalized cells and identify genes that might be responsible for the increased sensitivity of immortalized KC, we performed microarray analysis on primary and immortalized KC exposed to UVB. We found significant alterations in the expression of selective sets of genes involved in cellular structure/adhesion, DNA repair, transcription, differentiation, and apoptosis (Simbulan-Rosenthal et al, 2005). Three of the four known human inhibitors of differentiation and DNA binding (Id) genes , a class of helix-loop-helix (HLH) transcriptional repressors involved in differentiation, proliferation, apoptosis, and carcinogenesis were found to exhibit significant changes in expression following UVB exposure.…”

Section: Introductionmentioning

confidence: 99%

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Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

et al. 2006

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Inhibitor of differentiation/DNA binding (Id) proteins comprise a class of helix-loop-helix transcription factors involved in proliferation, differentiation, apoptosis, and carcinogenesis. We have shown that while Id2 is induced by UVB in primary keratinocytes, Id3 is upregulated only in immortalized cells. We have now determined that the consequences of ectopic expression of Id3 protein are strikingly different between immortalized and primary keratinocytes. Overexpression of Id3 induces a significant increase in apoptotic cells as revealed by Annexin V positivity as well as proteolytic processing of caspase-3 in immortalized, but not in primary keratinocytes. Id3-green fluorescent protein (GFP)-positive cells exhibited a fivefold increase in apoptotic nuclear fragmentation compared to Id3-GFP-negative cells. These apoptotic responses were accompanied by activation of caspase-3, as shown by immunocytochemical staining with antibodies to active caspase-3. Immunostaining with antibodies to the active form of caspase-9 as well as to the active form of Bax further revealed that induction of apoptosis in Id3-overexpressing keratinocytes occurred via a mitochondrial-caspase-9-mediated pathway. Coexpression of dominant-negative caspase-9 with Id3 significantly suppressed apoptotic nuclear fragmentation, indicating that caspase-9 activation is essential for Id3-induced cell death. This response was also markedly attenuated by coexpression with the Bax antagonist antiapoptotic protein Bcl2, confirming a role for Bax activation in this apoptotic response. Id3-induced Bax activation may result from increased expression of Bax protein. Furthermore, reduction of Id3 expression by small interfering RNAs abrogated the UVB-induced proteolytic activation of caspase-3 in these cells. These data together suggest that UVB-induced apoptosis of immortalized keratinocytes is at least in part due to Id3 upregulation in these cells.

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Id2 protein is selectively upregulated by UVB in primary, but not in immortalized human keratinocytes and inhibits differentiation

Cited by 18 publications

References 85 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

Functional Gene Expression Analysis Uncovers Phenotypic Switch in Aggressive Uveal Melanomas

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

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