The AMP-activated protein kinase beta 1 subunit modulates erythrocyte integrity

Cambridge, Emma L.; McIntyre, Zoe; Clare, Simon; Arends, Mark J.; Goulding, David; Isherwood, Christopher; Caetano, Susana S.; Reviriego, Carmen Ballesteros; Swiaţkowska, A; Kane, Leanne; Adams, David J.; White, Jacqueline K.; Speak, Anneliese O.

doi:10.1016/j.exphem.2016.09.006

Cited by 8 publications

(4 citation statements)

References 13 publications

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“…Prkab1 heterozygous KO mice have no previous described role in ciliary biology in vertebrates or humans (Table S1). A previously reported Prkab1 KO mouse had splenomegaly, anemia, and erythrocyte morphologic abnormalities; a cluster of pathologies consistent with hemolytic anemia 51 . Prkab1 is a part of the beta subunit of serine/threonine AMP-activated protein kinase, a heterotrimeric complex containing a catalytic alpha subunit paired with beta and gamma regulatory subunits.…”

Section: Discussionmentioning

confidence: 78%

Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes

Higgins

Moore

Berberovic

et al. 2022

Sci Rep

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We searched a database of single-gene knockout (KO) mice produced by the International Mouse Phenotyping Consortium (IMPC) to identify candidate ciliopathy genes. We first screened for phenotypes in mouse lines with both ocular and renal or reproductive trait abnormalities. The STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains in order to generate a list of “candidate ciliopathy genes.” From this list, 32 genes encoded proteins predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology. Histological and morphological evidence of phenotypes found in ciliopathies in knockout mouse lines are presented as examples (genes Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1). Phenotyping data and descriptions generated on IMPC mouse line are useful for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. Here we demonstrate the effective use of the IMPC phenotype data to uncover genes with no previous role in ciliary biology, which may be clinically relevant for identification of novel disease genes implicated in ciliopathies.

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Section: Discussionmentioning

confidence: 78%

Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes

Higgins

Moore

Berberovic

et al. 2022

Sci Rep

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“…Ampk α1 −/− , Ampk β1 − / − and Ampk γ1 −/− mice develop hemolytic anemia, and the plasma membrane of their red blood cells shows elasticity defects. 5–8 The membrane composition evolves continuously throughout erythropoiesis and during red blood cell maturation; the defects due to the absence of Ampk are most likely initiated during erythropoiesis. We, therefore, studied the role of AMPK during human erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Ampkα1 −/− and Ampkγ1 −/− erythrocytes were highly resistant to osmotic stress and poorly deformable in response to increasing shear stress, which is consistent with a loss of membrane elasticity. 5–8…”

Section: Introductionmentioning

confidence: 99%

Finely-tuned regulation of AMP-activated protein kinase is crucial for human adult erythropoiesis

et al. 2018

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AMP-activated protein kinase (AMPK) is a heterotrimeric complex containing α, β, and γ subunits involved in maintaining integrity and survival of murine red blood cells. Indeed, Ampk α 1 −/− , Ampk β1 −/− and Ampk γ1 −/− mice develop hemolytic anemia and the plasma membrane of their red blood cells shows elasticity defects. The membrane composition evolves continuously along erythropoiesis and during red blood cell maturation; defects due to the absence of Ampk could be initiated during erythropoiesis. We, therefore, studied the role of AMPK during human erythropoiesis. Our data show that AMPK activation had two distinct phases in primary erythroblasts. The phosphorylation of AMPK (Thr172) and its target acetyl CoA carboxylase (Ser79) was elevated in immature erythroblasts (glycophorin A low ), then decreased conjointly with erythroid differentiation. In erythroblasts, knockdown of the α1 catalytic subunit by short hairpin RNA led to a decrease in cell proliferation and alterations in the expression of membrane proteins (band 3 and glycophorin A) associated with an increase in phosphorylation of adducin (Ser726). AMPK activation in mature erythroblasts (glycophorin A high ), achieved through the use of direct activators (GSK621 and compound 991), induced cell cycle arrest in the S phase, the induction of autophagy and caspase-dependent apoptosis, whereas no such effects were observed in similarly treated immature erythroblasts. Thus, our work suggests that AMPK activation during the final stages of erythropoiesis is deleterious. As the use of direct AMPK activators is being considered as a treatment in several pathologies (diabetes, acute myeloid leukemia), this observation is pivotal. Our data highlighted the importance of the finely-tuned regulation of AMPK during human erythropoiesis.

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“…This means that increases in tumorigenesis and reduced survival in p53−/− AMPK β1−/− could have been due to other factors besides the primary lesion. For example, AMPK α1, β1, and γ1 null mice have been shown to have increased red blood cell fragility, which causes microcytic anemia and splenomegaly without altering the number of leukocytes (Cambridge et al ., 2017; Föller et al ., 2009; Foretz et al ., 2010, 2011). We also observed splenomegaly in our AMPK β1 null mice (Table S2) so it is possible that this could have an impact on tumorigenesis and lifespan of p53−/− AMPK β1−/− mice.…”

Section: Discussionmentioning

confidence: 99%

AMPK β1 reduces tumor progression and improves survival in p53 null mice

Houde

Donzelli²,

Sacconi³

et al. 2017

Molecular Oncology

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The AMP‐activated protein kinase (AMPK) is a heterotrimeric protein complex that is an important sensor of cellular energy status. Reduced expression of the AMPK β1 isoform has been linked to reduced survival in different cancers, but whether this accelerates tumor progression and the potential mechanism mediating these effects are not known. Furthermore, it is unknown whether AMPK β1 is implicated in tumorigenesis, and if so, what tissues may be most sensitive. In the current study, we find that in the absence of the tumor suppressor p53, germline genetic deletion of AMPK β1 accelerates the appearance of a T‐cell lymphoma that reduces lifespan compared to p53 deficiency alone. This increased tumorigenesis is linked to increases in interleukin‐1β (IL1β), reductions in acetyl‐CoA carboxylase (ACC) phosphorylation, and elevated lipogenesis. Collectively, these data indicate that reductions in the AMPK β1 subunit accelerate the development of T‐cell lymphoma, suggesting that therapies targeting this AMPK subunit or inhibiting lipogenesis may be effective for limiting the proliferation of p53‐mutant tumors.

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The AMP-activated protein kinase beta 1 subunit modulates erythrocyte integrity

Cited by 8 publications

References 13 publications

Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes

Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes

Finely-tuned regulation of AMP-activated protein kinase is crucial for human adult erythropoiesis

AMPK β1 reduces tumor progression and improves survival in p53 null mice

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