Knockdown of PRKAR2B Results in the Failure of Oocyte Maturation

Yoon, Hyung Ku; Jang, Hoon; Kim, Eun Young; Moon, Sohyeon; Lee, Sang-Ho; Cho, Minha; Cho, Hye‐Kyung; Ko, Jung Jae; Chang, Eun Mi; Lee, Kyung‐Ah; Choi, Youngsok

doi:10.1159/000487978

Cited by 13 publications

(8 citation statements)

References 43 publications

(43 reference statements)

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“…There are four different regulatory subunits (RIα, RIβ, RIIα and RIIβ) of PKA in human mammalian tissues 7 . Protein kinase cAMP‐dependent regulatory type II beta (PRKAR2B) plays a role in oocyte maturation, 8 regulates murine and human adipocyte differentiation 9 and inhibits the effect of cAMP responsive element binding protein (CREB) activity in T cells 10 . Recently, we identified PRKAR2B as a novel oncogene implicated in the development of CRPC 11,12 .…”

Section: Introductionmentioning

confidence: 99%

PRKAR2B‐HIF‐1α loop promotes aerobic glycolysis and tumour growth in prostate cancer

et al. 2020

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Objectives Reprogramming of cellular metabolism is profoundly implicated in tumorigenesis and can be exploited to cancer treatment. Cancer cells are known for their propensity to use glucose‐dependent glycolytic pathway instead of mitochondrial oxidative phosphorylation for energy generation even in the presence of oxygen, a phenomenon known as Warburg effect. The type II beta regulatory subunit of protein kinase A (PKA), PRKAR2B, is highly expressed in castration‐resistant prostate cancer (CRPC) and contributes to tumour growth and metastasis. However, whether PRKAR2B regulates glucose metabolism in prostate cancer remains largely unknown. Materials and methods Loss‐of‐function and gain‐of‐function studies were used to investigate the regulatory role of PRKAR2B in aerobic glycolysis. Real‐time qPCR, Western blotting, luciferase reporter assay and chromatin immunoprecipitation were employed to determine the underlying mechanisms. Results PRKAR2B was sufficient to enhance the Warburg effect as demonstrated by glucose consumption, lactate production and extracellular acidification rate. Mechanistically, loss‐of‐function and gain‐of‐function studies showed that PRKAR2B was critically involved in the tumour growth of prostate cancer. PRKAR2B was able to increase the expression level of hypoxia‐inducible factor 1α (HIF‐1α), which is a key mediator of the Warburg effect. Moreover, we uncovered that HIF‐1α is a key transcription factor responsible for inducing PRKAR2B expression in prostate cancer. Importantly, inhibition of glycolysis by the glycolytic inhibitor 2‐deoxy‐d‐glucose (2‐DG) or replacement of glucose in the culture medium with galactose (which has a much lower rate than glucose entry into glycolysis) largely compromised PRKAR2B‐mediated tumour‐promoting effect. Similar phenomenon was noticed by genetic silencing of HIF‐1α. Conclusions Our study identified that PRKAR2B‐HIF‐1α loop enhances the Warburg effect to enable growth advantage in prostate cancer.

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Section: Introductionmentioning

confidence: 99%

PRKAR2B‐HIF‐1α loop promotes aerobic glycolysis and tumour growth in prostate cancer

et al. 2020

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“…5 ) [ 1 , 51 , 52 ]. In this study, we found, for the first time, that the expression of RAB5B [ 53 ] which promotes the degradation of damaged mitochondria was decreased, the expression of PPP2R2A [ 54 ] which represses BAX, and the expression of PRKAR2B [ 55 , 56 ] which represses BAX via the pentose phosphate pathway were decreased in the cerebral blood vessels of ADNC +/CAA + patients (Fig. 4 ).…”

Section: Resultsmentioning

confidence: 81%

Proteomics-based investigation of cerebrovascular molecular mechanisms in cerebral amyloid angiopathy by the FFPE-LMD-PCT-SWATH method

Handa

Sasaki

Takao

et al. 2022

Fluids Barriers CNS

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Background Cerebral amyloid angiopathy (CAA) occurs in 80% of patients with Alzheimer’s disease (AD) and is mainly caused by the abnormal deposition of Aβ in the walls of cerebral blood vessels. Cerebrovascular molecular mechanisms in CAA were investigated by using comprehensive and accurate quantitative proteomics. Methods Concerning the molecular mechanisms specific to CAA, formalin-fixed paraffin-embedded (FFPE) sections were prepared from patients having AD neuropathologic change (ADNC) with severe cortical Aβ vascular deposition (ADNC +/CAA +), and from patients having ADNC without vascular deposition of Aβ (ADNC +/CAA −; so called, AD). Cerebral cortical vessels were isolated from FFPE sections using laser microdissection (LMD), processed by pressure cycling technology (PCT), and applied to SWATH (sequential window acquisition of all theoretical fragment ion spectra) proteomics. Results The protein expression levels of 17 proteins in ADNC +/CAA +/H donors (ADNC +/CAA + donors with highly abundant Aβ in capillaries) were significantly different from those in ADNC +/CAA − and ADNC −/CAA − donors. Furthermore, we identified 56 proteins showing more than a 1.5-fold difference in average expression levels between ADNC +/CAA + and ADNC −/CAA − donors, and were significantly correlated with the levels of Aβ or Collagen alpha-2(VI) chain (COL6A2) (CAA markers) in 11 donors (6 ADNC +/CAA + and 5 ADNC −/CAA −). Over 70% of the 56 proteins showed ADNC +/CAA + specific changes in protein expression. The comparative analysis with brain parenchyma showed that more than 90% of the 56 proteins were vascular-specific pathological changes. A literature-based pathway analysis showed that 42 proteins are associated with fibrosis, oxidative stress and apoptosis. This included the increased expression of Heat shock protein HSP 90-alpha, CD44 antigen and Carbonic anhydrase 1 which are inhibited by potential drugs against CAA. Conclusions The combination of LMD-based isolation of vessels from FFPE sections, PCT-assisted sample processing and SWATH analysis (FFPE-LMD-PCT-SWATH method) revealed for the first time the changes in the expression of many proteins that are involved in fibrosis, ROS production and cell death in ADNC +/CAA + (CAA patients) vessels. The findings reported herein would be useful for developing a better understanding of the pathology of CAA and for promoting the discovery and development of drugs and biomarkers for CAA.

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“…during oocyte metabolism ( 61 ). Similarly, the expression of PRDX2 in external vesicles has been suggested as a predictor of embryo implantation ability ( 62 ), while RFX1 and PRKA2 were related to embryonic development failure and lethality in mice ( 63 , 64 ). The fact that none of these genes were mentioned as pivotal infertility processes suggests that they may be involved in the modulation of fertility in mares by a polygenic pathway, via small genetic effects ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

Fine-Scale Analysis of Runs of Homozygosity Islands Affecting Fertility in Mares

Laseca

Molina²,

Ramón³

et al. 2022

Front. Vet. Sci.

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The loss of genetic variability in livestock populations bred under strict selection processes is a growing concern, as it may lead to increased inbreeding values and lower fertility, as a consequence of the “inbreeding depression” effect. This is particularly important in horses, where inbreeding levels tend to rise as individuals become more and more closely related. In this study, we evaluated the effect of increased inbreeding levels on mare fertility by combining an SNP-based genomic approach using runs of homozygosity and the estimation of genetic breeding values for reproductive traits in a large population of Pura Raza Española mares. Our results showed a negative correlation between whole-genome homozygosity and fertility estimated breeding values (EBVs) at the genome level (ρ = −0.144). However, the analysis at chromosome level revealed a wide variability, with some chromosomes showing higher correlations than others. Interestingly, the correlation was stronger (−0.241) when we repeated the analysis in a reduced dataset including the 10% most and least fertile individuals, where the latter showed an increase in average inbreeding values (FROH) of around 30%. We also found 41 genomic regions (ROHi, runs of homozygosity islands) where homozygosity increased 100-fold, 13 of which were significantly associated with fertility after cross-validation. These regions encompassed 17 candidate genes previously related to oocyte and embryo development in several species. Overall, we demonstrated the relationship between increased homozygosis at the genomic level and fertility in mares. Our findings may help to deal with the occurrence of inbreeding depression, as well as further our understanding of the mechanisms underlying fertility in mares.

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Knockdown of PRKAR2B Results in the Failure of Oocyte Maturation

Cited by 13 publications

References 43 publications

PRKAR2B‐HIF‐1α loop promotes aerobic glycolysis and tumour growth in prostate cancer

PRKAR2B‐HIF‐1α loop promotes aerobic glycolysis and tumour growth in prostate cancer

Proteomics-based investigation of cerebrovascular molecular mechanisms in cerebral amyloid angiopathy by the FFPE-LMD-PCT-SWATH method

Fine-Scale Analysis of Runs of Homozygosity Islands Affecting Fertility in Mares

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