scholarly journals Distinct, opposing functions for CFIm59 and CFIm68 in mRNA alternative polyadenylation of Pten and in the PI3K/Akt signalling cascade

2021 ◽  
Author(s):  
Hsin-Wei Tseng ◽  
Anthony Mota-Sydor ◽  
Rania Leventis ◽  
Ivan Topisirovic ◽  
Thomas F. Duchaine
Keyword(s):  
Alternative Polyadenylation ◽  
Regulatory Elements ◽  
Differential Regulation ◽  
Akt Pathway ◽  
Pten Protein ◽  
Regulatory Subunits ◽  
Factor I ◽  
Phosphoinositide 3 Kinase ◽  
Post Transcriptional Regulation ◽  
Signalling Cascade

ABSTRACTThe precise maintenance of PTEN dosage is crucial for tumor suppression across a wide variety of cancers. Post-transcriptional regulation of Pten heavily relies on regulatory elements encoded by its 3’UTR. We previously reported the important diversity of 3’UTR isoforms of Pten mRNAs produced through alternative polyadenylation (APA). Here, we reveal the direct regulation of Pten APA by the mammalian cleavage factor I (CFIm) complex, which in turn contributes to PTEN protein dosage. CFIm consists of the UGUA-binding CFIm25 and APA regulatory subunits CFIm59 or CFIm68. Deep sequencing analyses of perturbed (KO and KD) cell lines uncovered the differential regulation of Pten APA by CFIm59 and CFIm68 and further revealed that their divergent functions have widespread impact for APA in transcriptomes. Differentially regulated genes include numerous factors within the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway that PTEN counter-regulates. We further reveal a stratification of APA dysregulation among a subset of PTEN-driven cancers, with recurrent alterations among PI3K/Akt pathway genes regulated by CFIm. Our results refine the transcriptome selectivity of the CFIm complex in APA regulation, and the breadth of its impact in PTEN-driven cancers.

Signalling specificity in the Akt pathway in breast cancer

2014 ◽  
Vol 42 (5) ◽  
pp. 1349-1355 ◽  
Author(s):  
Abbe R. Clark ◽  
Alex Toker
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Akt Pathway ◽  
Cellular Processes ◽  
Akt Isoforms ◽  
Isoform Specificity ◽  
Novel Targets ◽  
Phosphoinositide 3 Kinase ◽  
Protein Kinase Akt ◽  
Signalling Cascade

Aberrant activation of fundamental cellular processes, such as proliferation, migration and survival, underlies the development of numerous human pathophysiologies, including cancer. One of the most frequently hyperactivated pathways in cancer is the phosphoinositide 3-kinase (PI3K)/Akt signalling cascade. Three isoforms of the serine/threonine protein kinase Akt (Akt1, Akt2 and Akt3) function to regulate cell survival, growth, proliferation and metabolism. Strikingly, non-redundant and even opposing functions of Akt isoforms in the regulation of phenotypes associated with malignancy in humans have been described. However, the mechanisms by which Akt isoform-specificity is conferred are largely unknown. In the present review, we highlight recent findings that have contributed to our understanding of the complexity of Akt isoform-specific signalling and discussed potential mechanisms by which this isoform-specificity is conferred. An understanding of the mechanisms of Akt isoform-specificity has important implications for the development of isoform-specific Akt inhibitors and will be critical to finding novel targets to treat disease.

scholarly journals Elevated levels of IL-1β in Fanconi anaemia group A patients due to a constitutively active phosphoinositide 3-kinase-Akt pathway are capable of promoting tumour cell proliferation

2009 ◽  
Vol 422 (1) ◽  
pp. 161-170 ◽  
Author(s):  
Ana Ibáñez ◽  
Paula Río ◽  
José Antonio Casado ◽  
Juan Antonio Bueren ◽  
José Luis Fernández-Luna ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Bone Marrow Failure ◽  
Nuclear Factor Κb ◽  
Hereditary Disease ◽  
Akt Pathway ◽  
Fanconi Anaemia ◽  
Primary Glioblastoma ◽  
A Cells ◽  
Group A ◽  
Phosphoinositide 3 Kinase

FA (Fanconi anaemia) is a hereditary disease characterized by congenital malformations, progressive bone marrow failure and an extraordinary elevated predisposition to develop cancer. In the present manuscript we describe an anomalous high level of the proinflammatory cytokine IL-1β (interleukin-1β) present in the serum of FA patients. The elevated levels of IL-1β were completely reverted by transduction of a wild-type copy of the FancA cDNA into FA-A (FA group A) lymphocytes. Although the transcription factor NF-κB (nuclear factor-κB) is a well established regulator of IL-1β expression, our experiments did not show any proof of elevated NF-κB activity in FA-A cells. However, we found that the overexpression of IL-1β in FA-A cells is related to a constitutively activated PI3K (phosphoinositide 3-kinase)-Akt pathway in these cells. We provide evidence that the effect of Akt on IL-1β activation is mediated by the inhibition of GSK3β (glycogen synthase kinase 3β). Finally, our data indicate that the levels of IL-1β produced by FA-A lymphoblasts are enough to promote an activation of the cell cycle in primary glioblastoma progenitor cells. Together, these results demonstrate that the constitutive activation of the PI3K-Akt pathway in FA cells upregulates the expression of IL-1β through an NF-κB-independent mechanism and that this overproduction activates the proliferation of tumour cells.

FOXD3 inhibits cell proliferation, migration, and invasion in nasopharyngeal carcinoma through regulation of the PI3K–Akt pathway

2020 ◽  
Vol 98 (6) ◽  
pp. 653-660 ◽  
Author(s):  
Xiaoxing Xie ◽  
Gaoyun Xiong ◽  
Wenjun Chen ◽  
Hongdan Fu ◽  
Mingqian Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nasopharyngeal Carcinoma ◽  
Cell Apoptosis ◽  
Inhibitory Effect ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Inhibitory Effects ◽  
Protein Levels ◽  
Flow Cytometric ◽  
Phosphoinositide 3 Kinase

FOXD3 has been found previously to positively regulate miR-26b, a tumor inhibitor of nasopharyngeal carcinoma (NPC). However, FOXD3’s precise function and associated mechanism of action in NPC have not yet been investigated. In this study, the expression of FOXD3 mRNA and protein was evaluated using RT-qPCR, western blotting, and immunohistochemistry. Protein levels involved in the phosphoinositide 3-kinase – protein kinase B (PI3K–Akt) pathway were assessed by western blot, and cell proliferation was determined by MTT and colony forming assays. Additionally, cell apoptosis was assessed by flow cytometric assay. Finally, the migration and invasion capabilities of the NPC cells were determined using wound healing and Transwell assays. We found that FOXD3 levels were relatively low in NPC tissue and cells, while an increase caused the inhibition of the PI3K–Akt pathway. Functional experiments found that overexpression of FOXD3 suppressed cell proliferation, migration, and invasion and enhanced cell apoptosis in NPC C6661 cells. IGF-1, an activator of the PI3K–Akt pathway, reversed the inhibitory effect of FOXD3. Furthermore, we found upregulation of the PI3K–Akt pathway and upregulation of the inhibitory effects of FOXD3 on C6661 cellular activities. In conclusion, FOXD3 negatively affected the PI3K–Akt pathway to restrain the processes involved in C6661 cell pathology. These findings further exposed the function and downstream axis of FOXD3 in NPC and displayed a promising new target for NPC therapy.

scholarly journals Transcription of the Human 5-Hydroxytryptamine Receptor 2B (HTR2B) Gene Is under the Regulatory Influence of the Transcription Factors NFI and RUNX1 in Human Uveal Melanoma

2018 ◽  
Vol 19 (10) ◽  
pp. 3272 ◽  
Author(s):  
Manel Benhassine ◽  
Sylvain Guérin
Keyword(s):  
Transcription Factors ◽  
Uveal Melanoma ◽  
Serotonin Receptor ◽  
Molecular Mechanisms ◽  
Regulatory Region ◽  
Gene Signature ◽  
Regulatory Elements ◽  
Gene Encoding ◽  
Aberrant Expression ◽  
Factor I

Because it accounts for 70% of all eye cancers, uveal melanoma (UM) is therefore the most common primary ocular malignancy. In this study, we investigated the molecular mechanisms leading to the aberrant expression of the gene encoding the serotonin receptor 2B (HTR2B), one of the most discriminating among the candidates from the class II gene signature, in metastatic and non-metastatic UM cell lines. Transfection analyses revealed that the upstream regulatory region of the HTR2B gene contains a combination of alternative positive and negative regulatory elements functional in HTR2B− but not in HTR23B+ UM cells. We demonstrated that both the transcription factors nuclear factor I (NFI) and Runt-related transcription factor I (RUNX1) interact with regulatory elements from the HTR2B gene to either activate (NFI) or repress (RUNX1) HTR2B expression in UM cells. The results of this study will help understand better the molecular mechanisms accounting for the abnormal expression of the HTR2B gene in uveal melanoma.

scholarly journals A standard knockout procedure alters expression of adjacent loci at the translational level

2021 ◽  
Author(s):  
Artyom A Egorov ◽  
Alexander I Alexandrov ◽  
Valery N Urakov ◽  
Desislava S Makeeva ◽  
Roman O Edakin ◽  
...  
Keyword(s):  
Genetic Interaction ◽  
Gene Annotation ◽  
Alternative Polyadenylation ◽  
Mrna Translation ◽  
Regulatory Elements ◽  
Ribosome Profiling ◽  
Head Orientation ◽  
Neighboring Gene ◽  
Knockout Mutants ◽  
Severe Impairment

Abstract The Saccharomyces cerevisiae gene deletion collection is widely used for functional gene annotation and genetic interaction analyses. However, the standard G418-resistance cassette used to produce knockout mutants delivers strong regulatory elements into the target genetic loci. To date, its side effects on the expression of neighboring genes have never been systematically assessed. Here, using ribosome profiling data, RT-qPCR, and reporter expression, we investigated perturbations induced by the KanMX module. Our analysis revealed significant alterations in the transcription efficiency of neighboring genes and, more importantly, severe impairment of their mRNA translation, leading to changes in protein abundance. In the ‘head-to-head’ orientation of the deleted and neighboring genes, knockout often led to a shift of the transcription start site of the latter, introducing new uAUG codon(s) into the expanded 5′ untranslated region (5′ UTR). In the ‘tail-to-tail’ arrangement, knockout led to activation of alternative polyadenylation signals in the neighboring gene, thus altering its 3′ UTR. These events may explain the so-called neighboring gene effect (NGE), i.e. false genetic interactions of the deleted genes. We estimate that in as much as ∼1/5 of knockout strains the expression of neighboring genes may be substantially (>2-fold) deregulated at the level of translation.

scholarly journals A p53-Phosphoinositide Signalosome Regulates Nuclear Akt Activation

2021 ◽  
Author(s):  
Mo Chen ◽  
Suyong Choi ◽  
Tianmu Wen ◽  
Changliang Chen ◽  
Narendra Thapa ◽  
...  
Keyword(s):  
Genotoxic Stress ◽  
Akt Pathway ◽  
Mutant P53 ◽  
Tumor Suppressor P53 ◽  
Wild Type ◽  
Akt Activation ◽  
Pi3k Inhibitors ◽  
Phosphoinositide 3 Kinase ◽  
Induced Apoptosis ◽  
Dependent Mechanism

The tumor suppressor p53 and the phosphoinositide 3-kinase (PI3K)-Akt pathway have fundamental roles in regulating cell growth, apoptosis and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear Akt activation by a p53-dependent mechanism that is independent from the canonical membrane-localized PI3K-Akt pathway. Upon genotoxic stress a nuclear p53-PI3,4,5P3 complex is generated in regions devoid of membranes by a nuclear PI3K, and this complex recruits all the kinases required to activate Akt and phosphorylate FOXOs, inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear Akt in an on/off fashion upon stress, whereas mutant p53 stimulates high basal Akt activity, indicating a fundamental difference. The nuclear p53-phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, underscoring its therapeutic relevance.

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