Mechanisms of impaired differentiation in rhabdomyosarcoma

Keller, Charles; Guttridge, Denis C.

doi:10.1111/febs.12421

Cited by 103 publications

(111 citation statements)

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“…In exon skipping-treated human DMD myoblasts, miR-31 inhibition increased dystrophin rescue, indicating that interfering miR-1 and miR-206 are both repressed in rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma (32,33). RMS is also characterized by the overexpression of early myogenic markers including desmin, myogenin, and myogenic differentiation-1 (MyoD) (33), which are trapped in a nonfunctional state, thereby inhibiting terminal differentiation of myogenic progenitor cells (34). Even though the roles of miR-1 and miR-206 in RMS are still not well defined, several studies suggest that they play an important role in the pathogenesis of this cancer.…”

Section: Micrornasmentioning

confidence: 99%

Non-coding RNAs in muscle differentiation and musculoskeletal disease

Ballarino

Morlando

Fatica

et al. 2016

Journal of Clinical Investigation

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Section: Micrornasmentioning

confidence: 99%

Non-coding RNAs in muscle differentiation and musculoskeletal disease

Ballarino

Morlando

Fatica

et al. 2016

Journal of Clinical Investigation

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“…The resulting PAX3/FOXO1 fusion protein exhibits a greater than 100-fold gain-of-function effect on PAX3 downstream target genes and a dominant-negative effect on wild-type PAX3 expression (Bennicelli et al, 1996). Cellular pathways and mechanisms affected by aberrant PAX3:FOXO1 expression include MET signalling (which stimulates cell cycle following postnatal muscle injury), FGF receptor 4-and IGF receptor-mediated growth, and chromatin remodelling, which allows activation of MYOD1 target genes (Keller and Guttridge, 2013).…”

Section: Aberrant Pax Gene Expression: Implications For Regeneration mentioning

confidence: 99%

Pax genes: regulators of lineage specification and progenitor cell maintenance

2014

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Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. We also discuss mechanistic insights into the roles of Pax genes in regeneration and in adult diseases, including cancer. KEY WORDS: Pax genes, Embryogenesis, Lineage determination IntroductionPaired box (Pax) genes encode transcription factors that contain a highly conserved DNA-binding domain called the paired domain (PD, Fig. 1A) and can be considered to be a principle regulator of gene expression. Nine Pax genes (Pax1-Pax9) have been characterised in mammals and the evolutionary conserved paired domain has been identified across phylogenies from insects, to amphibians and birds. In higher vertebrates, PAX proteins are subclassified into groups according to inclusion of an additional DNA-binding homeodomain and/or an octapeptide region, which serves as a binding motif for protein co-factors for potent inhibition of downstream gene transcription (Eberhard et al., 2000) (Fig. 1B); all PAX proteins include a transactivation domain located within the C-terminal amino acids (Underhill, 2012). It is also known that all Pax genes, with the exception of Pax4 and Pax9, produce alternative RNA transcripts (see Table 1). The functional diversity of Pax proteins in vivo is thus linked to the ability to produce alternatively spliced gene products that differ in structure and, consequently, in the binding activity of their paired and homeodomain DNA-binding regions (Underhill, 2012).Three decades ago, the characterisation and roles of Pax genes in embryonic development began to unfold. Early studies discovered that regulatory gene families such as the Pax family are involved in the sequential compartmentalisation and body patterning of developing organisms; thereafter, studies highlighted a role for Pax genes in the early specification of cell fate and the subsequent morphogenesis of various tissues and organs. Following this, mutational studies of Pax genes confirmed the importance of these regulatory roles in the PRIMER School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.*Author for correspondence (j.blake@ecu.edu.au) This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.initiation and progression of ...

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“…Pax3-Foxo1 orchestrates the expression of numerous Pax3 downstream genes with increased amplitude and without feedback control, impairing the apoptosis and differentiation processes [49][50][51][52][53] and conferring a G2 checkpoint-dependent resistance to irradiation in vitro and in vivo. 54 For example, the Pax3-Foxo1-dependent transcription of genes like hepatocyte growth factor receptor (HGFR or c-MET), FGFR4, IGF-2 and C-X-C chemokine receptor type 4 (CXCR4) contributes to increase tumor aggressiveness and metastasis recurrence.…”

Section: Pax3-foxo1 Oncoproteinmentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies

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Mechanisms of impaired differentiation in rhabdomyosarcoma

Cited by 103 publications

References 119 publications

Non-coding RNAs in muscle differentiation and musculoskeletal disease

Non-coding RNAs in muscle differentiation and musculoskeletal disease

Pax genes: regulators of lineage specification and progenitor cell maintenance

Uncovering metabolism in rhabdomyosarcoma

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