Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Ge, Zheng; Gu, Yan; Han, Qi; Zhao, Gang; Li, Min; Li, Jianyong; Chen, Baoan; Sun, Tianyu; Dovat, Sinisa; Gale, Robert Peter; Song, Chunhua

doi:10.1038/srep38004

Cited by 27 publications

(32 citation statements)

References 48 publications

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“…Similarly, together with Cav-1, DNM2 also mediates effects on cancer formation and progression. The 2 proteins are involved in the endocytosis of a number of receptor proteins, ligands and signaling molecules (19,62). However, it has been suggested that there are several other interlinked signaling pathways that, in response to overexpression of Cav-1 and DNM2, may be activated and/or deactivated, resulting in tumor formation (63).…”

Section: Discussionmentioning

confidence: 99%

Caveolin‑1 and dynamin‑2 overexpression is associated with the progression of bladder cancer

et al. 2019

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Caveolae-mediated endocytosis regulates cell adhesion and growth in an anchorage-dependent manner. Studies of the endocytic function of caveolae have suggested a wide-ranging list of cargoes, including a number of receptors and extracellular proteins, ligands and nutrients from the extracellular matrix. Disruption of the processes of caveolae-mediated endocytosis mediated by signaling proteins is critical to cellular integrity. Caveolin-1 and dynamin-2 are the 2 major proteins associated with endocytotic function. Mechanistically, dynamin-2 has a co-equal role with caveolin-1 in terms of caveolae-derived endosome formation. Recent studies have revealed the pathological outcomes associated with the dysregulation of caveolin-1 and dynamin-2 expression. Increased expression levels of the gene for caveolin, Cav-1, resulting in augmented cellular metastasis and invasion, have been demonstrated in various types of cancer, and overexpression of the gene for dynamin-2, DNM2, has been associated with tumorigenesis in cervical, pancreatic and lung cancer. An increased expression of Cav-1 and DNM2 is known to be associated with the invasive behavior of cancer cells, and with cancer progression. Furthermore, it has been previously demonstrated that, in caveolar assembly and caveolae mediated endocytosis, Cav-1 interacts directly with DNM2 during the processes. Altered expression of the 2 genes is critical for the normal function of the cell. The expression patterns of Cav-1 and DNM2 have been previously examined in bladder cancer cell lines, and were each demonstrated to be overexpressed. In the present study, the expression levels of these 2 genes in bladder cancer samples were quantified. The gene expression levels of Cav-1 and DNM2 were identified to be increased 8.88-and 8.62-fold, respectively, in tumors compared with the normal controls. Furthermore, high-grade tumors exhibited significantly increased expression levels of Cav-1 and DNM2 (both P<0.0001) compared with the low-grade tumors. In addition, compared with normal control samples, the expression of the 2 genes in tumor samples was observed to be highly significant (P<0.0001), with a marked positive correlation identified for the tumors (Pearson's correlation coefficient, r=0.80 for the tumor samples vs. r=0.32 in the normal control samples). Taken together, the results of the present study demonstrated that the overexpression of Cav-1 and DNM2 genes, and a determination of their correlation coefficients, may be a potential risk factor for bladder cancer, in addition to other clinical factors.

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Section: Discussionmentioning

confidence: 99%

Caveolin‑1 and dynamin‑2 overexpression is associated with the progression of bladder cancer

et al. 2019

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“…Subsequent work confirmed the presence of the CK2-Ikaros signaling axis, and its role in regulating expression of a large number of tumor promoters and suppressors in pediatric and adult leukemia (Ge et al, 2015, 2016a, 2016b, 2016c, 2016d, 2017; Wang et al, 2016). Epigenetic analysis of the promoters of Ikaros target genes showed that CK2 regulates not only Ikaros DNA-binding affinity to promoters of its target genes, but also Ikaros-mediated recruitment of HDAC1, as well as the epigenetic signature at regulatory elements of Ikaros targets (Song et al, 2016).…”

Section: Ikzf1 (Ikaros)mentioning

confidence: 80%

Casein Kinase II (CK2), Glycogen Synthase Kinase-3 (GSK-3) and Ikaros mediated regulation of leukemia

Gowda

Soliman

Kapadia

et al. 2017

Advances in Biological Regulation

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Signaling networks that regulate cellular proliferation often involve complex interactions between several signaling pathways. In this manuscript we review the crosstalk between the Casein Kinase II (CK2) and Glycogen Synthase Kinase-3 (GSK-3) pathways that plays a critical role in the regulation of cellular proliferation in leukemia. Both CK2 and GSK-3 are potential targets for anti-leukemia treatment. Previously published data suggest that CK2 and GSK-3 act synergistically to promote the phosphatidylinositol-3 kinase (PI3K) pathway via phosphorylation of PTEN. More recent data demonstrate another mechanism through which CK2 promotes the PI3K pathway – via transcriptional regulation of PI3K pathway genes by the newly-discovered CK2-Ikaros axis. Together, these data suggest that the CK2 and GSK-3 pathways regulate AKT/PI3K signaling in leukemia via two complementary mechanisms: a) direct phosphorylation of PTEN and b) transcriptional regulation of PI3K-promoting genes. Functional interactions between CK2, Ikaros and GSK3 define a novel signaling network that regulates proliferation of leukemia cells. This regulatory network involves both direct posttranslational modifications (by CK and GSK-3) and transcriptional regulation (via CK2-mediated phosphorylation of Ikaros). This information provides a basis for the development of targeted therapy for leukemia.

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“…Ikaros binding to the promoter of DNM2 was observed in both B-ALL and T-ALL cells [108]. Overexpression of Ikaros in both types of leukemia resulted in reduced transcription of DNM2.…”

Section: Dynamin 2 (Dnm2)mentioning

confidence: 96%

“…The DNM2 protein has five domains: GTPase domain; intermediate domain (MD); pleckstrin homology domain (PH); GTPase effector domain (GED); and proline-arginine-rich domain (PRD). Recurrent mutations in all DNM2 domains including the GTPase domain have been linked to T-ALL [105][106][107][108][109]. It has been suggested that DNM2 plays a major role in the internalization of IL7R, TCR, and Notch ligand Delta like 1 (DIl-1), thereby triggering the development of ALL [110].…”

Section: Dynamin 2 (Dnm2)mentioning

confidence: 99%

Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

Dhanyamraju

Iyer

Smink

et al. 2020

IJMS

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Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide an overview of the role of Ikaros tumor suppressor and its role in regulation of gene transcription in acute leukemia. Ikaros (IKZF1) is a DNA-binding protein that functions as a master regulator of hematopoiesis and the immune system, as well as a tumor suppressor in acute lymphoblastic leukemia (ALL). Genetic alteration or functional inactivation of Ikaros results in the development of high-risk leukemia. Ikaros binds to the specific consensus binding motif at upstream regulatory elements of its target genes, recruits chromatin-remodeling complexes and activates or represses transcription via chromatin remodeling. Over the last twenty years, a large number of Ikaros target genes have been identified, and the role of Ikaros in the regulation of their expression provided insight into the mechanisms of Ikaros tumor suppressor function in leukemia. Here we summarize the role of Ikaros in the regulation of the expression of the genes whose function is critical for cellular proliferation, development, and progression of acute lymphoblastic leukemia.

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Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Cited by 27 publications

References 48 publications

Caveolin‑1 and dynamin‑2 overexpression is associated with the progression of bladder cancer

Caveolin‑1 and dynamin‑2 overexpression is associated with the progression of bladder cancer

Casein Kinase II (CK2), Glycogen Synthase Kinase-3 (GSK-3) and Ikaros mediated regulation of leukemia

Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

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