Growth Factor Independence 1 Antagonizes a p53-Induced DNA Damage Response Pathway in Lymphoblastic Leukemia

Khandanpour, Cyrus; Phelan, James D.; Vaßen, Lothar; Schütte, Judith; Chen, Riyan; Horman, Shane R.; Gaudreau, Marie-Claude; Krongold, Joseph; Zhu, Jinfang; Paul, William E.; Dührsen, Ulrich; Göttgens, Bertie; Grimes, H. Leighton; Möröy, Tarik

doi:10.1016/j.ccr.2013.01.011

Cited by 67 publications

(93 citation statements)

References 49 publications

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“…Staining of apoptotic cells and apoptotic bodies was similar when comparing PTTG-Tg mice (n ϭ 4) withWT mice (n ϭ 4) (1.05-fold change, P value not significant) ( Figure 5D, i and ii). The presence of apoptosis was also determined through measurement of mRNA levels of the proapoptotic genes bax and Bbc3 (Puma) (57,58). Results were similar when comparing hPTTG-Tg and WT mice (0.99-and 0.95-fold change, respectively, n ϭ 10, P value not significant) (Figure 5Diii).…”

Section: Hpttg Regulates Egf Expression and Secretion In Vivomentioning

confidence: 52%

Regulation of Pituitary Tumor Transforming Gene (PTTG) Expression and Phosphorylation in Thyroid Cells

et al. 2013

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Human pituitary tumor transforming gene (hPTTG) is a multifunctional proto-oncogene implicated in the initiation and progression of several tumors. Phosphorylation of hPTTG is mediated by cyclin-dependent kinase 2 (CDC2), whereas cellular expression is regulated by specificity protein 1 (SP1). The mechanisms underlying hPTTG propagation of aberrant thyroid cell growth have not been fully defined. We set out to investigate the interplay between hPTTG and growth factors, as well as the effects of phosphorylation and SP1 regulation on hPTTG expression and function. In our study, epidermal growth factor (EGF), TGF␣, and IGF-1 induced hPTTG expression and phosphorylation in thyroid cells, which was associated with activation of MAPK and phosphoinositide 3-kinase. Growth factors induced hPTTG independently of CDC2 and SP1 in thyroid carcinoma cells. Strikingly, CDC2 depletion in TPC-1 cells resulted in enhanced expression and phosphorylation of hPTTG and reduced cellular proliferation. In reciprocal experiments, hPTTG overexpression induced EGF, IGF-1, and TGF␣ mRNAs in primary human thyrocytes. Treatment of primary human thyrocytes with conditioned media derived from hPTTG-transfected cells resulted in autocrine upregulation of hPTTG protein, which was ameliorated by growth factor depletion or growth factor receptor tyrosine kinase inhibitors. A transgenic murine model of thyroid targeted hPTTG overexpression (hPTTG-Tg) (FVB/N strain, both sexes) demonstrated smaller thyroids with reduced cellular proliferation and enhanced secretion of Egf. In contrast, Pttg Ϫ/Ϫ knockout mice (c57BL6 strain, both sexes) showed reduced thyroidal Egf mRNA expression. These results define hPTTG as having a central role in thyroid autocrine signaling mechanisms via growth factors, with profound implications for promotion of transformed cell growth. (Endocrinology 154: 4408 -4422, 2013)

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Section: Hpttg Regulates Egf Expression and Secretion In Vivomentioning

confidence: 52%

Regulation of Pituitary Tumor Transforming Gene (PTTG) Expression and Phosphorylation in Thyroid Cells

et al. 2013

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“…[52][53][54] Similar analyses with murine Gfi1b-deficient HSCs, megakaryocytes, or erythroid cells demonstrated that Gfi1b helps to establish gene expression programs necessary for the development of both erythroid and megakaryocytic lineages 29,32,55 and confirms the complementary roles of Gfi1 and Gfi1b in hematopoiesis already suspected by their differential, cell type-specific expression pattern.…”

Section: 3944-48mentioning

confidence: 71%

“…72 Experiments with conditionally deficient mice have shown that Gfi1 is required for efficient T-cell tumorigenesis, regardless of whether malignant transformation was initiated retrovirally, by chemical carcinogenesis, or by Notch1 activation. 52 This effect could also be shown for human cells because inhibition of GFI1 in primary human T-ALL inhibited their expansion in immune-deficient mice. More specifically, this study provided evidence that Gfi1 is an "oncorequisite" factor required for T-cell lymphomagenesis by limiting the ability of p53 to induce apoptosis during malignant transformation; that is, loss of Gfi1 led to reactivation of p53 in T-cell tumor cells and induced cell death.…”

Section: Lymphoma and Leukemia T-cell Lymphoma And Acute T-cell Lymphmentioning

confidence: 94%

“…Comparison of gene expression profiles from T-ALL patients characterized by NOTCH1 mutation status and NOTCH1 target gene expression with those diagnosed of early T-cell precursor ALL showed that ETP-ALL patients had low levels of GFI1 expression compared with those with a NOTCH1 signature, where GFI1 expression was higher. 52 This suggested that GFI1 overexpression contributes to the process of malignant transformation in subsets of human T-ALL. Notably, during experimental T-cell tumorigenesis in mice, Gfi1 expression is maintained at high levels in the preleukemic phase but is downregulated upon development of a full-blown leukemia, suggesting that Gfi1 exerts a more complex function in tumorigenesis than can be inferred from a simple overexpression experiment.…”

Section: Lymphoma and Leukemia T-cell Lymphoma And Acute T-cell Lymphmentioning

confidence: 99%

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From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

Möröy

Vaßen

Wilkes

et al. 2015

Blood

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The DNA-binding zinc finger transcription factors Gfi1 and Gfi1b were discovered more than 20 years ago and are recognized today as major regulators of both early hematopoiesis and hematopoietic stem cells. Both proteins function as transcriptional repressors by recruiting histone-modifying enzymes to promoters and enhancers of target genes. The establishment of Gfi1 and Gfi1b reporter mice made it possible to visualize their cell type–specific expression and to understand their function in hematopoietic lineages. We now know that Gfi1 is primarily important in myeloid and lymphoid differentiation, whereas Gfi1b is crucial for the generation of red blood cells and platelets. Several rare hematologic diseases are associated with acquired or inheritable mutations in the GFI1 and GFI1B genes. Certain patients with severe congenital neutropenia carry mutations in the GFI1 gene that lead to the disruption of the C-terminal zinc finger domains. Other mutations have been found in the GFI1B gene in families with inherited bleeding disorders. In addition, the Gfi1 locus is frequently found to be a proviral integration site in retrovirus-induced lymphomagenesis, and new, emerging data suggest a role of Gfi1 in human leukemia and lymphoma, underlining the role of both factors not only in normal hematopoiesis, but also in a wide spectrum of human blood diseases.

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“…Together, GFI1/1B are activated in at least one-third of G3-MBs (80). In mouse models of acute lymphoblastic leukemia, Gfi1 restricts p53 activity by repressing its proapoptotic targets (81,82). In hematopoietic cells, Gfi1/1b recruit the corepressor CoREST, the histone demethylase LSD1, and histone deacetylases (HDACs) 1 and 2 to target promoters involved in lineage differentiation (83).…”

Section: Groupmentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, those who survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into the molecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies.

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Growth Factor Independence 1 Antagonizes a p53-Induced DNA Damage Response Pathway in Lymphoblastic Leukemia

Cited by 67 publications

References 49 publications

Regulation of Pituitary Tumor Transforming Gene (PTTG) Expression and Phosphorylation in Thyroid Cells

Regulation of Pituitary Tumor Transforming Gene (PTTG) Expression and Phosphorylation in Thyroid Cells

From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

Molecular mechanisms and therapeutic targets in pediatric brain tumors

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