Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors

Li, Jia; Roy, Sumedha; Kim, Youngmi; Li, Shibo; Zhang, Baojun; Love, Cassandra; Reddy, Anupama; Davé, Sandeep S.; Diehl, Anna Mae; Zhuang, Yuan

doi:10.4049/jimmunol.1601935

Cited by 15 publications

(9 citation statements)

References 99 publications

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“…Id3 has been reported to induce caspase3‐ and 9‐dependent apoptosis in human keratinocytes, and TRIB3 has been also reported to have an antiapoptotic role in gastric cancer cells exposed to anticancer drugs . Decreased Id3 and Atoh8 , and increased Trib3 were reported to be involved in tumor progression . Moreover, the analysis of human HCC data from TCGA disclosed that the increased expression of CD74 and TRIB3 and decreased expression of ATOH8 were also observed in human HCC, and the expression changes were related to poor prognosis (Figure ).…”

Section: Discussionmentioning

confidence: 98%

DNA methylation changes involved in the tumor increase in F2 males born to gestationally arsenite‐exposed F1 male mice

et al. 2019

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Multigenerational adverse effects from the environment such as nutrition and chemicals are among important concerns in environmental health issues. Previously, we have found that arsenite exposure of only F0 females during their pregnancy increases hepatic tumors in the F2 males in C3H mice. In the current study, we investigated the association of DNA methylation with the hepatic tumor increase in the F2 males of the arsenite group. Reduced‐representation bisulfite sequencing analysis newly identified that DNA methylation levels of regions around the transcriptional start sites of Tmem54 and Cd74 were decreased and the expression of these genes were significantly increased in the hepatic tumors of F2 males of the arsenite group. The associations between DNA methylation in these regions and gene expression changes were confirmed by treatment of murine hepatoma cell lines and hepatic stellate cell line with 5‐aza‐2′‐deoxycytidine. Overexpression of Cd74 in Hepa1c1c7 cells increased Trib3 expression and suppressed the expression of tumor suppressor genes Id3 and Atoh8. Human database analysis using the Cancer Genome Atlas indicated that TMEM54, CD74, and TRIB3 were significantly increased and that ATOH8 was decreased in hepatocellular carcinoma. The data also showed that high expression of TMEM54 and TRIB3 and low expression of ATOH8 were associated with poor survival. These results suggested that an increase in Tmem54 and Cd74 expression via DNA methylation reduction was involved in the tumor increase in the F2 male offspring by gestational arsenite exposure of F0 females. This study also suggested that genes downstream of Cd74 were involved in tumorigenesis.

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Section: Discussionmentioning

confidence: 98%

DNA methylation changes involved in the tumor increase in F2 males born to gestationally arsenite‐exposed F1 male mice

et al. 2019

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“…It is likely that the depletion of Id proteins unleashes the “early,” pre-TCR-independent developmental program for iNKT and other innate-like T cells, which otherwise occurs at much lower frequencies on a wild-type genetic background. Consequently, we have also observed heterogeneous innate-like αβ T cell lymphomas derived from iNKT, CD1dTet − , or T FH cells in Id2/Id3-deficient mice ( 14 , 39 ). Cumulatively, our findings support a layered ( 21 ), rather than a parallel developmental structure that coordinates the distinct fates of iNKT and conventional αβT cells during T cell development in the thymus.…”

Section: Discussionmentioning

confidence: 72%

“…The loss of iNKT cells in L-DKO CD1d −/− mice emphasizes the critical role of the selection step in iNKT cell development ( 39 ). However, TCRα repertoire sequencing of preselection DP cells from these mice demonstrated an increased frequency of Vα14-Jα18 rearrangements, suggesting that the lack of Id proteins can promote iNKT-specific rearrangements prior to, and independent of their selection.…”

Section: Discussionmentioning

confidence: 99%

Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection

et al. 2018

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A family of transcription factors known as E proteins, and their antagonists, Id proteins, regulate T cell differentiation at critical developmental checkpoints. Id proteins promote the differentiation of conventional αβ T cells and suppress the expansion of innate-like αβ T cells known as invariant natural killer T (iNKT) cells. However, it remains to be determined whether Id proteins differentially regulate these distinct lineage choices in early stages of T cell development. In this manuscript, we report that in Id-deficient mice, uninhibited activity of the E protein family member E2A mediates activation of genes that support iNKT cell development and function. There is also biased rearrangement in Id-deficient DP cells that promotes selection into the iNKT lineage in these mice. The observed expansion of iNKT cells is not abrogated by blocking pre-TCR signaling, which is required for conventional αβ T cell development. Finally, E2A is found to be a key transcriptional regulator of both iNKT and γδNKT lineages, which appear to have shared lineage history. Therefore, our study reveals a previously unappreciated role of E2A in coordinating the development of the iNKT lineage at an early stage, prior to their TCR-mediated selection alongside conventional αβ T cells.

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“…Id2 and/or Id3 also play tumor suppressor roles to prevent lymphomagenesis of gd, iNKT and innate-like T cells. In these studies, tumorigenesis can be attributed to direct dysregulation of cell cycle, NF-κB, cytokine-cytokine receptor interaction and innate-like developmental genes by high E2A activity [108][109][110]. Interestingly, although most lymphomas found in Id3-deficient mice are gdTCR + , some morphologically identical tumors express typical B cell markers, B220 and CD19 in the absence T cell-related markers [108].…”

Section: Discussionmentioning

confidence: 99%

“…However, an increase in Myc expression was observed among some samples [108]. We have recently found that Id2 and Id3 also play tumor suppressor roles in invariant natural killer T (iNKT-) and innate-like tumors in mice [109]. These lymphomas develop much more rapidly than the gdT cell lymphomas in Id3-deficient mice, and display signs of chromosomal instability.…”

Section: Paradoxical Role Of Id Proteins In T Cell Lymphomasmentioning

confidence: 99%

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

Roy

Zhuang

2018

Front. Med.

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A family of transcription factors known as Id proteins, or inhibitor of DNA binding and differentiation, is capable of regulating cell proliferation, survival and differentiation, and is often upregulated in multiple types of tumors. Due to their ability to promote self-renewal, Id proteins have been considered as oncogenes, and potential therapeutic targets in cancer models. On the contrary, certain Id proteins are reported to act as tumor suppressors in the development of Burkitt's lymphoma in humans, and hepatosplenic and innate-like T cell lymphomas in mice. The contexts and mechanisms by which Id proteins can serve in such contradictory roles to determine tumor outcomes are still not well understood. In this review, we explore the roles of Id proteins in lymphocyte development and tumorigenesis, particularly with respect to inhibition of their canonical DNA binding partners known as E proteins. Transcriptional regulation by E proteins, and their antagonism by Id proteins, act as gatekeepers to ensure appropriate lymphocyte development at key checkpoints. We re-examine the derailment of these regulatory mechanisms in lymphocytes that facilitate tumor development. These mechanistic insights can allow better appreciation of the context-dependent roles of Id proteins in cancers and improve considerations for therapy.

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Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors

Cited by 15 publications

References 99 publications

DNA methylation changes involved in the tumor increase in F2 males born to gestationally arsenite‐exposed F1 male mice

DNA methylation changes involved in the tumor increase in F2 males born to gestationally arsenite‐exposed F1 male mice

Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

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