Transforming Growth Factor-β-mediated p15INK4BInduction and Growth Inhibition in Astrocytes Is SMAD3-dependent and a Pathway Prominently Altered in Human Glioma Cell Lines

Rich, Jeremy; Zhang, Ming; Datto, Michael B.; Bigner, Darell D.; Wang, Xiao Fan

doi:10.1074/jbc.274.49.35053

Cited by 111 publications

(96 citation statements)

References 39 publications

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“…We complemented our exogenous GATA4 overexpression results above with endogenous regulation of GATA4 and its growth effects on astrocytes. We focused on TGF-b as GATA4 induced p15Ink4b, known to be regulated by TGF-b, including in astrocytes (Hannon and Beach, 1994;Quelle et al, 1995) (Rich et al, 1999). We found TGF-b stimulation induced GATA4 expression in astrocytes, a result which was also supported by studies in regulation of gastrointestinal differentiation genes (Afouda et al, 2005;Anttonen et al, 2006;Belaguli et al, 2007).…”

Section: Discussionsupporting

confidence: 65%

“…The anti-proliferative effect of TGFb was also partially blocked with GATA4 siRNA as were p15INK4B levels, suggesting that the TGF-binduced anti-proliferation effect may be partially mediated through GATA4 in astrocytes. The SMAD 2/3/4 transcription factor complex is another potent activator of p15INK4B (Rich et al, 1999) and could explain why loss of GATA4 did not completely reduce p15INK4B levels and the anti-proliferative phenotype of TGF-b. Taken together, our observations suggest a model where GATA4 mediates its anti-proliferation effect through induction of p15INK4B and its proapoptotic effect through elevated levels of activated Caspase 3/7, Figure 8e.…”

Section: Discussionmentioning

confidence: 99%

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GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

et al. 2009

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The GATA transcription factors consist of six family members, which bind to the consensus DNA-binding element, W-GATA-R, and are poorly characterized in the central nervous system (CNS). Using retroviral gene trapping on transgenic mouse glioma models, we identified GATA6 to be a novel tumor suppressor gene in glioblastoma multiforme. We now show GATA4, a family member of GATA6, to be expressed in the neurons and glia of normal murine and human embryonic and adult CNS. Silencing GATA4 in normal astrocytes did not alter their growth properties. In contrast, knockdown of Gata4 in p53 null non-transformed murine astrocytes induced transformation, with increased proliferation and resistance to chemotherapy or radiation-induced apoptosis. Furthermore, GATA4 expression was lost in a panel of human malignant astrocytoma cell lines. GATA4 overexpression in normal human and murine astrocytes resulted in a cell cycle block in G1 phase, with increased apoptosis. Mechanistically, GATA4 was a transcriptional inducer of the cyclin-dependent kinase inhibitor, p15INK4B, leading to the attenuation of cyclin D1. GATA4 expression was also induced by transforming growth factor-b, leading to the inhibition of astrocyte proliferation. Collectively, we show that GATA4 is expressed in the embryonic and adult CNS and acts as a negative regulator of astrocyte proliferation and growth.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

et al. 2009

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“…In most cell types, TGFβ is a potent inhibitor of cell growth, arresting cell cycle progression in late G 1 phase. This growth suppression is associated with the increased expression or activities of several cyclindependent kinase inhibitors, including p15, p21 and p27 (Rich et al, 1999). Critical mutations in the TGFβ pathway should also lead to the loss of the ability of the cell to undergo apoptosis.…”

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confidence: 99%

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

Francis-Thickpenny

Richardson

et al. 2001

Br J Cancer

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Summary Epithelial ovarian carcinoma is often diagnosed at an advanced stage of disease and is the leading cause of death from gynaecological neoplasia. The genetic changes that occur during the development of this carcinoma are poorly understood. It has been proposed that IGFIIR, TGFβ1 and TGFβRII act as a functional unit in the TGFβ growth inhibitory pathway, and that somatic loss-of-function mutations in any one of these genes could lead to disruption of the pathway and subsequent loss of cell cycle control. We have examined these 3 genes in 25 epithelial ovarian carcinomas using single-stranded conformational polymorphism analysis and DNA sequence analysis. A total of 3 somatic missense mutations were found in the TGFβRII gene, but none in IGFRII or TGFβ1. An association was found between TGFβRII mutations and histology, with 2 out of 3 clear cell carcinomas having TGFβRII mutations. This data supports other evidence from mutational analysis of the PTEN and β-catenin genes that there are distinct developmental pathways responsible for the progression of different epithelial ovarian cancer histologic subtypes.

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“…The induction of p15INK4b is SMAD3-dependent. Indeed, TGFβ fails to induce p15INK4b and to inhibit astrocytic growth in Smad3-null mice compared to the wild-type (Rich et al, 1999). The induction of p21WAF1/CIP1 by the SMAD3/SMAD4 complex requires Foxo as a co-factor, which is negatively controlled by the growthpromoting PI3K pathway as well as the telencephalic development factor FoxG1 (Seoane et al, 2004).…”

Section: Tgfβ Subfamily In Glioblastoma Biologymentioning

confidence: 99%

Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression

Nana¹,

Yang²,

Lin³

2015

Asian Pacific Journal of Cancer Prevention

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Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor β (TGFβ) superfamily is a large group of structurally related proteins including TGFβ subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (GDF). It is involved in important biological functions including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The TGFβ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulinlike growth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases (MMPs), "pro-neoplastic" integrins (αvβ3, α5β1) and GBM initiating cells (GICs) as well as inducing a GBMmesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the TGFβ subfamily yields advantageous results, enhancing BMPs production is also beneficial.

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Transforming Growth Factor-β-mediated p15INK4BInduction and Growth Inhibition in Astrocytes Is SMAD3-dependent and a Pathway Prominently Altered in Human Glioma Cell Lines

Cited by 111 publications

References 39 publications

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression

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