Human neuroblastomas with unfavorable biologies express high levels of brain-derived neurotrophic factor mRNA and a variety of its variants

Aoyama, Mineyoshi; Asai, Kiyofumi; Shishikura, Tomotane; Kawamoto, Takemasa; Miyachi, Taishi; Yokoi, Takashi; Togari, Hajime; Wada, Yoshiro; Kato, Taiji; Nakagawara, Akira

doi:10.1016/s0304-3835(00)00715-1

Cited by 79 publications

(90 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The human BDNF gene consists of seven upstream noncoding exons differentially spliced to the downstream coding exon, producing multiple transcripts (Aoyama et al, 2001;Garzon et al, 2002;Liu et al, 2005) (see Fig. 1 A).…”

Section: Introductionmentioning

confidence: 99%

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

Garzon¹,

Fahnestock²

2007

J. Neurosci.

170

127

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a senile dementia characterized by amyloid plaques, neurofibrillary tangles, and synaptic and cell loss. The "amyloid cascade" hypothesis suggests that amyloid-␤ (A␤), the peptide deposited as amyloid plaques, is the primary insult in AD. However, debate continues over the mechanism of A␤ toxicity and whether fibrillar or oligomeric A␤ is the active species of the peptide that ultimately causes the synaptic loss and dementia associated with AD. Brain-derived neurotrophic factor (BDNF) is required for survival and function of cells compromised in AD. Decreased BDNF causes defects in long-term potentiation and memory and correlates with cognitive decline. We previously demonstrated that BDNF reduction occurs early in the course of AD, suggesting that decreased BDNF may promote neuronal dysfunction in AD. We also demonstrated that three of seven human BDNF transcripts are specifically downregulated in AD. What pathological feature(s) of AD leads to the decreased BDNF is unknown.In this study, we administered both fibrillar and oligomeric conformations of A␤ 1-42 to differentiated SH-SY5Y, a human neuroblastoma cell line, and measured both phosphorylated cAMP response element-binding protein (CREB), a regulator of BDNF transcription, and BDNF total mRNA. We found that oligomeric but not fibrillar preparations of A␤ 1-42 significantly decrease both phosphorylated CREB and total BDNF mRNA. Furthermore, oligomeric A␤ 1-42 decreases BDNF transcripts IV and V in these cells, demonstrating that A␤ 1-42 downregulates the major BDNF transcript decreased in vivo in the AD brain. Thus, oligomeric A␤ 1-42 could compromise neuronal function, causing memory loss and cognitive dysfunction by downregulation of BDNF in AD.

show abstract

Section: Introductionmentioning

confidence: 99%

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

Garzon¹,

Fahnestock²

2007

J. Neurosci.

170

127

View full text Add to dashboard Cite

show abstract

“…In contrast, children older than 1 year diagnosed with NB often experience aggressive tumors that are disseminated, resistant to chemotherapy, and metastasized to bone, and often fatal. An important correlative characteristic of NB is the expression of two of the neurotrophin receptors, the TrkA/nerve growth factor (NGF) receptor and the TrkB/brain-derived neurotrophic factor receptor (1)(2)(3)(4). The expression of TrkB, a poor prognosis marker, mediates survival, proliferation, and chemotherapeutic drug resistance (5-10), whereas expression of TrkA, a favorable prognosis marker, induces cell growth arrest and differentiation of cultured NB cells (11)(12)(13).…”

mentioning

confidence: 99%

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

Lavoie

LeSauteur

Kohn

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Neuroblastoma (NB) is the most frequent solid extracranial tumor in children. Its clinical prognosis correlates with the expression of members of the Trk neurotrophin receptor family, which includes TrkA and TrkB. TrkA expression is associated with favorable prognosis, whereas TrkB expression is associated with poor prognosis. Here we show that TrkA expression induces the apoptosis of NB cells and does so by modulating the levels or activities of a number of proteins involved in regulating cell survival and apoptosis, including p53, Bcl-2, and caspase-3. TrkA increased the expression of p53 target proteins and failed to induce apoptosis in cells where p53 was inactivated by mutation or via expression of dominant inhibitory p53 or E1B55K, indicating that TrkA mediates apoptosis, at least in part, through p53. Treatment with a caspase inhibitor or overexpression of Bcl-X L also prevented TrkA from inducing apoptosis. In contrast, elevated expression of TrkA in non-transformed sympathetic neurons resulted in the suppression of p53 levels and enhanced survival. These results identify apoptosis as a novel biological response of TrkA in NB cells and imply that TrkA is a good prognosis marker for NB due in part to its ability to mediate apoptosis when expressed at sufficient levels. Neuroblastoma (NB)1 is the most common solid extracranial solid tumor of childhood and likely arises from sympathoadrenal precursor cells. The median age at diagnosis is ϳ18 months, and spontaneous tumor regression is frequently observed in patients diagnosed at 1 year of age or younger. In contrast, children older than 1 year diagnosed with NB often experience aggressive tumors that are disseminated, resistant to chemotherapy, and metastasized to bone, and often fatal. An important correlative characteristic of NB is the expression of two of the neurotrophin receptors, the TrkA/nerve growth factor (NGF) receptor and the TrkB/brain-derived neurotrophic factor receptor (1-4). The expression of TrkB, a poor prognosis marker, mediates survival, proliferation, and chemotherapeutic drug resistance (5-10), whereas expression of TrkA, a favorable prognosis marker, induces cell growth arrest and differentiation of cultured NB cells (11)(12)(13). This is consistent with TrkA being expressed in tumors that spontaneously regress. Most NB cell lines, which are derived from malignant tumors, lack or have very low levels of TrkA protein expression. Cell lines with low TrkA expression respond to NGF by differentiating into neuronal-like cells (11). Similarly, expression of TrkA by transfection converts NGF non-responsive NB cells into NGF-responsive cells, both in culture and in vivo, with the typical responses being the cessation of cell growth and differentiation into neural and Schwann cells (12). Thus, TrkA converts malignant NB cells into quiescent differentiated cells.An alternative or additional explanation for why TrkA is a good prognosis marker for NB that might contribute to spontaneous tumor regression is that it may induce apoptosis. Paradoxic...

show abstract

“…Expression of TrkB and BDNF is usually detected in primary neuroblastomas with an unfavorable outcome such as highly invasive and metastatic capacity (2,5,6). We investigated the molecular mechanisms how TrkB expression contributed to cell survival.…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports showed that both TrkB and BDNF were frequently overexpressed in various cancers, such as pancreatic carcinoma, prostate carcinoma, Wilms' tumor and neuroblastomas, particularly those with aggressive behavior and poor prognosis (5)(6)(7)(8). It was also reported that the activation of TrkB induced malignant transformation of the epithelial cells through MEK and PI3K/Akt signaling (9).…”

Section: Introductionmentioning

confidence: 99%

Neurotrophic receptor tyrosine kinase B sxinduces c-fos-associated cell survival

Hayashi

Nakatani²,

Nishioka³

et al. 2009

Int J Mol Med

View full text Add to dashboard Cite

Abstract. The neurotrophic receptor tyrosine kinase B (TrkB) is a cell surface receptor for brain-derived neurotrophic factor (BDNF) with kinase activity. This protein is expressed in various tumors and thought to participate in various cellular processes. In this study, we established 293T cells stably expressing human TrkB to elucidate its intracellular functions. Using this cell system, we examined the biological roles of TrkB and its downstream target molecules. The TrkB expressing cells showed an increased survival rate through increased c-fos mRNA expression by BDNF, which were completely suppressed by TrkB inhibitor. Moreover, the combination of inhibitors of mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) partially reduced both the cell survival rate and c-fos mRNA expression, whereas monotreatment of these reagents could not affect cell survival nor c-fos mRNA expression. These results suggested that TrkB could play a role in c-fos-associated cell survival through both MEK and PI3K pathway. It is conceivable that activation of TrkB has a significant impact on tumorigenesis and metastasis.

show abstract

Human neuroblastomas with unfavorable biologies express high levels of brain-derived neurotrophic factor mRNA and a variety of its variants

Cited by 79 publications

References 24 publications

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

Neurotrophic receptor tyrosine kinase B sxinduces c-fos-associated cell survival

Contact Info

Product

Resources

About