A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC)

Sandoval, Imelda T.; Delacruz, Richard Glenn C; Miller, Braden N.; Hill, Shauna; Olson, Kristofor A.; Gabriel, Ana E.; Boyd, Kevin; Satterfield, Christeena; Remmen, Holly Van; Rutter, Jared; Jones, David A.

doi:10.7554/elife.22706

Cited by 29 publications

(22 citation statements)

References 47 publications

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“…APC similarly regulates CtBP1 expression in human colon cancer cell lines [91], indicating that the zebrafish mechanism by which it drives differentiation through retinoic acid biosynthesis may be present in the human colorectal epithelium as well. Studies from the zebrafish model also indicate that impaired intestinal differentiation following Apc loss is mediated in part by a decrease in the expression of mitochondrial pyruvate carrier 1 ( Mpc1 ), resulting in defective pyruvate metabolism that is independent of the WNT pathway and potentially linked to the Warburg effect [94]. Since differentiation and cell migration along the crypt-villus axis are coupled processes [95], APC may help link cell fate and cell migration in the colorectal epithelium.…”

Section: The Role Of Apc In Differentiationmentioning

confidence: 99%

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

Hankey

Frankel

Groden

2018

Cancer Metastasis Rev

148

110

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The acquisition of biallelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. APC encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor β-catenin; APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting β-catenin in the nucleus. APC also suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA. Mutations in APC are often frameshifts, insertions or deletions that introduce premature stop codons and lead to the production of truncated APC proteins that lack its normal functions and possess tumorigenic properties. Therapeutic approaches in development for the treatment of APC-deficient tumors are focused on the inhibition of canonical WNT signaling, especially through targets downstream of APC in the pathway, or on the restoration of wild-type APC expression.

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Section: The Role Of Apc In Differentiationmentioning

confidence: 99%

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

Hankey

Frankel

Groden

2018

Cancer Metastasis Rev

148

110

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“…In particular, glycolysis was shown to be characteristic of 5 self-renewing stem cells and of different types of progenitors, such as neuronal and 6 hematopoietic progenitor cells [1,2]. It has been demonstrated that stem cells tend to 7 switch from glycolytic metabolism toward mitochondrial oxidative phosphorylation 8 (OXPHOS) while they differentiate [3][4][5]. Accordingly, it was suggested that a balance 9 between glycolysis and OXPHOS metabolism could somehow guide the choice between 10 self-renewal and differentiation in stem cells fate [6].…”

mentioning

confidence: 99%

Erythroid differentiation displays a peak of energy consumption concomitant with glycolytic metabolism rearrangements

Angélique

Vallin

Romestaing

et al. 2019

Preprint

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Author summarySingle-cell based gene expression data from one of our previous publication pointed out significant variations of LDHA level, an important metabolism player, during erythroid differentiation. Deeper investigations highlighted that a metabolic switch occurred along differentiation of erythroid cells as previously emphasized in stem cell differentiation. More precisely our finding showed that self-renewing progenitor cells relied mostly upon a glycolytic, lactate-productive, metabolism and required LDHA activity, whereas differentiating cells, mainly involved the aerobic mitochondrial oxidative phosphorylation (OXPHOS). However our careful kinetic study demonstrated that these metabolic rearrangements were coming along with a particular temporary event, occurring within the first 24h of erythroid differentiation. The activity of glycolytic metabolism and OXPHOS rose jointly with ATP production at 12-24h of the differentiation process before lactate-productive glycolysis sharply fall down and energy needs decline. Finally, our results showed that the metabolic switch mediated through LDHA drop and OXPHOS upkeep might be necessary for erythroid differentiation. We also discuss the possibility that metabolism, gene expression and epigenetics could act together in a circular manner as a driving force for differentiation. Introduction 1Metabolism is a biological process mostly involved in energy consumption, production 2 and distribution, which is essential for cell functions and survival.3 An emerging theme is the possible causal involvement of metabolic changes during a 4 differentiation process. In particular, glycolysis was shown to be characteristic of 5 self-renewing stem cells and of different types of progenitors, such as neuronal and 6 hematopoietic progenitor cells [1,2]. It has been demonstrated that stem cells tend to 7 switch from glycolytic metabolism toward mitochondrial oxidative phosphorylation 8 (OXPHOS) while they differentiate [3][4][5]. Accordingly, it was suggested that a balance 9 between glycolysis and OXPHOS metabolism could somehow guide the choice between 10 self-renewal and differentiation in stem cells fate [6]. It has also been demonstrated that 11 preventing the shutting down of the glycolytic pathway was detrimental for neuronal 12 differentiation [4]. Otherwise, regarding somatic cells reprogramming into induced 13 pluripotent stem cells, it has been reported that pluripotency induction required the 14 concomitant upregulation of glycolytic metabolism and downregulation of OXPHOS [7]. 15 Regarding erythroid differentiation, progenitors depend on glycolysis and present a 16 Warburg-like profile as they display a high proliferation rate and produce an abundant 17 amount of lactate [8]. However, few is known about glucose metabolism behavior during 18 erythroid differentiation, when compared to erythroid progenitors self-renewal. Mature 19 mammals erythrocytes were shown to rely upon lactate dehydrogenase to fulfill their 20 functions, depending therefore upon the glycolytic p...

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“…Tiene una prevalencia de 1 cada 10.000 individuos y una incidencia en la población española de 2,8 por cada 100.000 habitantes (35). En la mayoría de los pacientes los pólipos empiezan a desarrollarse durante la segunda década de la vida y, en todos los casos, los pacientes sin tratamiento desarrollan tumores entre los 40 y los 50 años (36). El patrón de herencia para la PAF es autosómico dominante, por lo que en las familias portadoras de una mutación asociada a este síndrome existe una fuerte agregación, aunque aproximadamente un 25% de los casos son causados por mutaciones de novo (35).…”

Section: B) Poliposisunclassified

“…El 30% de las familias afectadas con PAFA no presentan mutaciones en el gen APC, pero presentan mutaciones en el gen MYH; en estos casos, el síndrome se denomina Poliposis Adenomatosa asociada al gen MYH (PAM) y presenta un patrón de herencia autosómico recesivo (36,39). Además de los síndromes mencionados anteriormente, en la tabla 3 se incluyen diferentes tipos de poliposis gastrointestinales asociados al riesgo de padecer CCR, dentro de los cuales se incluye el síndrome de Peutz-Jeghers, la Poliposis Familiar Juvenil y Poliposis Hiperplásica, el síndrome de Codwen y Poliposis asociada a los genes que codifican la DNA polimerasa.…”

Section: Figura 5 Colectomía De Un Paciente Con Paf Que Muestra Innunclassified

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Nuevas aproximaciones en el estudio de la ruta autofágica en cáncer colorrectal

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A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC)

Cited by 29 publications

References 47 publications

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

Erythroid differentiation displays a peak of energy consumption concomitant with glycolytic metabolism rearrangements

Nuevas aproximaciones en el estudio de la ruta autofágica en cáncer colorrectal

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