Deregulated expression of pro-survival and pro-apoptotic p53-dependent genes upon Elongator deficiency in colon cancer cells

Cornez, Isabelle; Creppe, Catherine; Gillard, Magali; Hennuy, Benoît; Chapelle, Jean-Paul; Dejardin, Emmanuel; Merville, Marie‐Paule; Close, Pierre; Chariot, Alain

doi:10.1016/j.bcp.2008.03.006

Cited by 19 publications

(12 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased cell death at the same developmental stage leading to developmental delay was also reported in embryos lacking the human Bloom syndrome gene [46]. Also, further support for a putative role of IKAP in regulation of cell death or proliferation is enhanced by the findings that elimination of IKAP in vitro enhances basal expression of pro-apoptotic p53-dependent genes [47] and decreases expression of genes involved in cell proliferation [17].…”

Section: Discussionmentioning

confidence: 62%

Deletion of Exon 20 of the Familial Dysautonomia Gene Ikbkap in Mice Causes Developmental Delay, Cardiovascular Defects, and Early Embryonic Lethality

et al. 2011

View full text Add to dashboard Cite

Familial Dysautonomia (FD) is an autosomal recessive disorder that affects 1/3,600 live births in the Ashkenazi Jewish population, and leads to death before the age of 40. The disease is characterized by abnormal development and progressive degeneration of the sensory and autonomic nervous system. A single base pair substitution in intron 20 of the Ikbkap gene accounts for 98% of FD cases, and results in the expression of low levels of the full-length mRNA with simultaneous expression of an aberrantly spliced mRNA in which exon 20 is missing. To date, there is no animal model for the disease, and the essential cellular functions of IKAP - the protein encoded by Ikbkap - remain unknown. To better understand the normal function of IKAP and in an effort to generate a mouse model for FD, we have targeted the mouse Ikbkap gene by homologous recombination. We created two distinct alleles that result in either loss of Ikbkap expression, or expression of an mRNA lacking only exon 20. Homozygosity for either mutation leads to developmental delay, cardiovascular and brain malformations, accompanied with early embryonic lethality. Our analyses indicate that IKAP is essential for expression of specific genes involved in cardiac morphogenesis, and that cardiac failure is the likely cause of abnormal vascular development and embryonic lethality. Our results also indicate that deletion of exon 20 abolishes gene function. This implies that the truncated IKAP protein expressed in FD patients does not retain any significant biological function.

show abstract

Section: Discussionmentioning

confidence: 62%

Deletion of Exon 20 of the Familial Dysautonomia Gene Ikbkap in Mice Causes Developmental Delay, Cardiovascular Defects, and Early Embryonic Lethality

et al. 2011

View full text Add to dashboard Cite

show abstract

“…We previously showed that Elongator deficiency actually slightly stabilized p53 in colon cancer-derived HCT116 cells, but that it did not impair DNA damage-induced p53 phosphorylation (52). We also demonstrated that some p53 target genes were aberrantly expressed upon Elongator deficiency, which indicated that this acetylase complex protects cells from an inappropriate expression of p53-dependent genes rather than promoting p53 activation.…”

Section: Discussionmentioning

confidence: 93%

DERP6 (ELP5) and C3ORF75 (ELP6) Regulate Tumorigenicity and Migration of Melanoma Cells as Subunits of Elongator

Gillard

Ladang

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background:Elongator is an acetylase complex that regulates cell migration. Results: DERP6 (ELP5) and C3ORF75 (ELP6) are characterized as Elongator subunits that control cell motility and tumorigenicity of melanoma cells. ELP5 ensures Elongator integrity by connecting ELP3 to ELP4. Conclusion: ELP5 and ELP6 are new players for migration and tumorigenicity of transformed cells. Significance: Elongator may be involved in both tumor initiation and progression.

show abstract

“…IKAP-depletion has been shown to increase levels of pro-apoptotic genes such as Bax in colon cancer-derived cells and to alter levels of a number of pro-apoptotic genes in FD stem cells [41], [42] and may explain the developmental delay and early death observed in IKAP null mice [40]. Yeast two hybrid studies have identified binding of IKAP/Elp1 to BAT-3, an apoptosis regulatory gene [43].…”

Section: Discussionmentioning

confidence: 99%

IKAP/Elp1 Is Required In Vivo for Neurogenesis and Neuronal Survival, but Not for Neural Crest Migration

Hunnicutt¹,

Chaverra²,

George³

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

Familial Dysautonomia (FD; Hereditary Sensory Autonomic Neuropathy; HSAN III) manifests from a failure in development of the peripheral sensory and autonomic nervous systems. The disease results from a point mutation in the IKBKAP gene, which encodes the IKAP protein, whose function is still unresolved in the developing nervous system. Since the neurons most severely depleted in the disease derive from the neural crest, and in light of data identifying a role for IKAP in cell motility and migration, it has been suggested that FD results from a disruption in neural crest migration. To determine the function of IKAP during development of the nervous system, we (1) first determined the spatial-temporal pattern of IKAP expression in the developing peripheral nervous system, from the onset of neural crest migration through the period of programmed cell death in the dorsal root ganglia, and (2) using RNAi, reduced expression of IKBKAP mRNA in the neural crest lineage throughout the process of dorsal root ganglia (DRG) development in chick embryos in ovo. Here we demonstrate that IKAP is not expressed by neural crest cells and instead is expressed as neurons differentiate both in the CNS and PNS, thus the devastation of the PNS in FD could not be due to disruptions in neural crest motility or migration. In addition, we show that alterations in the levels of IKAP, through both gain and loss of function studies, perturbs neuronal polarity, neuronal differentiation and survival. Thus IKAP plays pleiotropic roles in both the peripheral and central nervous systems.

show abstract

Deregulated expression of pro-survival and pro-apoptotic p53-dependent genes upon Elongator deficiency in colon cancer cells

Cited by 19 publications

References 47 publications

Deletion of Exon 20 of the Familial Dysautonomia Gene Ikbkap in Mice Causes Developmental Delay, Cardiovascular Defects, and Early Embryonic Lethality

Deletion of Exon 20 of the Familial Dysautonomia Gene Ikbkap in Mice Causes Developmental Delay, Cardiovascular Defects, and Early Embryonic Lethality

DERP6 (ELP5) and C3ORF75 (ELP6) Regulate Tumorigenicity and Migration of Melanoma Cells as Subunits of Elongator

IKAP/Elp1 Is Required In Vivo for Neurogenesis and Neuronal Survival, but Not for Neural Crest Migration

Contact Info

Product

Resources

About