Transcriptional profiling of the Sonic hedgehog response: A critical role  for N-myc in proliferation of neuronal precursors

Oliver, Trudy G.; Grasfeder, Linda L.; Carroll, Audra L.; Kaiser, Constanze; Gillingham, Christine L.; Lin, Simon; Wickramasinghe, Rasika S.; Scott, Matthew P.; Wechsler‐Reya, Robert J.

doi:10.1073/pnas.0832317100

Cited by 333 publications

(290 citation statements)

References 39 publications

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“…Furthermore, Math1, a known marker of external granule layer cells of the cerebellum (Lee et al, 2005) and the putative progenitor cell of origin for medulloblastoma (Flora et al, 2009;Ayrault et al, 2010), showed increased expression in the CD133 þ stem-like cells. Lastly, known Hh target gene N-myc (Oliver et al, 2003) shows increased transcript levels in the CD133 þ Hh-receiving cells. These data, together with experiments performed on primary human medulloblastoma BTICs (Figure 4), allowed us to propose a model of cell-cell interactions that may occur between the CD133 þ BTIC and supportive CD133À cells within the tumor niche (Figure 5c).…”

Section: Shh Regulates Bmi1 In Medulloblastoma Btics X Wang Et Almentioning

confidence: 94%

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

et al. 2011

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Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathwaydriven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell-cell interaction between the CD133 þ Hh receptor cells and the CD133À Hh-secreting cells.

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Section: Shh Regulates Bmi1 In Medulloblastoma Btics X Wang Et Almentioning

confidence: 94%

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

et al. 2011

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“…Shh could be controlling proliferation by inducing FGF signaling and subsequently activating cyclin genes indirectly. However, it is also possible that Shh may have an FGF-independent role in regulating cell cycle progression, since it has been demonstrated that Shh is able to regulate key cyclin genes or other important cell cycle regulators, including phosphatases in different contexts (Dahmane and Ruiz i Altaba, 1999;Wallace, 1999;Wechsler-Reya and Scott, 1999;Kenney and Rowitch, 2000;Barnes et al, 2001;Kenney et al, 2003;Oliver et al, 2003;Cayuso et al, 2006;Yu et al, 2006). Recent evidence from studies in the mouse retina have shown that activation of the Hh pathway acts in a cellautonomous manner to up-regulate cyclinD1 and increase progenitor cell proliferation (Yu et al, 2006).…”

Section: Fgf and Shh Display Proliferative Effects During Retina Regementioning

confidence: 99%

Fibroblast growth factor–hedgehog interdependence during retina regeneration

Spence

Aycinena

Rio‐Tsonis

2007

Developmental Dynamics

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“…Interestingly, increased expression of cMyc has been linked to poor prognosis, independent of gene amplification (Herms et al, 2000;Grotzer et al, 2001). Because cMyc expression is known to be induced by activation of the Wnt pathway and nMyc by Shh/PTCH Kenney et al, 2003;Oliver et al, 2003), these data collectively implicate Myc as a common regulatory element in the control of medulloblastoma growth.…”

Section: Developmental Mechanisms Promote the Growth Of Medulloblastomentioning

confidence: 83%

Neural development and the ontogeny of central nervous system tumors

Pomeroy

2004

Neuron Glia Biol.

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Recent evidence argues that the oncogenesis and growth of CNS tumors occurs through dysregulated molecular and cellular mechanisms of neural development. New insights have emerged that have had a significant impact on both research and treatment of these cancers. Clinical presentation of brain tumors and conventional therapeuticsPrimary tumors of the CNS are the most common solid tumors of childhood and a major source of mortality and neurological disability for people of all ages. Their incidence is 5-15/100 000 person-years. Currently, there are ~360 000 people living with a brain tumor in the United States, including 26 000 children (CBTRUS, 2002).Children with a malignant brain tumor have an estimated 5-year-survival rate of 60%; survival rates decline progressively with age to reach a level of >5% for those older than 65 years. For each individual, survival probability is linked closely with histological type. Although there are many histological types of CNS neoplasms recognized by the World Health Organization (WHO), this review will focus primarily on astrocytomas and medulloblastomas, which account for ~75% of tumors in children, and astrocytomas/oligodendrogliomas, which comprise >50% of all tumors in adults (Kleihues and Cavenee, 2000). Brain tumors are further classified into histological grades that generally correlate with biological behavior. Low-grade tumors (WHO grades I and II) are comprised of neoplastic cells with relatively compact and homogenous nuclei and cytological differentiation reminiscent of their normal cells of origin. High-grade tumors diverge from the appearance of their cells of origin. For example, anaplastic (less differentiated) astrocytomas (WHO grade III) have atypical pleomorphic nuclei, poorly differentiated cytoplasm and high rates of proliferation as evident by the presence of mitoses. The most malignant tumors (WHO grade IV) have extremely atypical nuclei and very high Correspondence should be addressed to:

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Transcriptional profiling of the Sonic hedgehog response: A critical role for N-myc in proliferation of neuronal precursors

Abstract: neuron ͉ cerebellum ͉ granule cell

Cited by 333 publications

References 39 publications

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Fibroblast growth factor–hedgehog interdependence during retina regeneration

Neural development and the ontogeny of central nervous system tumors

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