scholarly journals Extracellular and subcellular regulation of the PI3K/Akt cassette: new mechanisms for controlling insulin and growth factor signalling

2007 ◽  
Vol 35 (2) ◽  
pp. 219-221 ◽  
Author(s):  
C. Wilson ◽  
N. Vereshchagina ◽  
B. Reynolds ◽  
D. Meredith ◽  
C.A.R. Boyd ◽  
...  
Keyword(s):  
Cellular Response ◽  
Human Cancer ◽  
Molecular Genetic ◽  
Cell Types ◽  
Cellular Functions ◽  
Genetic Studies ◽  
Downstream Effects ◽  
Growth Factor Signalling ◽  
Cell Type Specific ◽  
Phosphoinositide 3 Kinase

The PI3K (phosphoinositide 3-kinase)/Akt (also called protein kinase B) signalling cassette plays a central role in the response to growth factors, particularly insulin-like molecules, and its misregulation is a characteristic feature of diabetes and many forms of human cancer. Recent molecular genetic studies initiated in the fruitfly, Drosophila melanogaster, have highlighted two new cell-type-specific mechanisms regulating PI3K/Akt signalling and its downstream effects. First, the cellular response to this cassette is modulated by several classes of cell-surface transporters and sensors, suggesting an important role for extracellular nutrients in insulin-sensitivity. Secondly, various cell types show a markedly different subcellular distribution of the activated kinase Akt, influencing the cellular functions of this molecule. These findings reveal new mechanisms by which processes such as growth, lipogenesis and insulin resistance can be differentially regulated and may suggest novel strategies for treating insulin-linked diseases.

p38 Mitogen-Activated Protein Kinase and Hematologic Malignancies

2009 ◽  
Vol 133 (11) ◽  
pp. 1850-1856
Author(s):  
Yongdong Feng ◽  
Jianguo Wen ◽  
Chung-Che(Jeff) Chang
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Cell Types ◽  
Hematologic Malignancies ◽  
Mapk Signaling ◽  
Chemotherapeutic Agents ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Functions ◽  
Downstream Effects ◽  
Mitogen Activated Protein

Abstract Context.—p38 mitogen-activated protein kinase (MAPK) signaling has been implicated in responses ranging from apoptosis to cell cycle, induction of expression of cytokine genes, and differentiation. This plethora of activators conveys the complexity of the p38 pathway. This complexity is further complicated by the observation that the downstream effects of p38 MAPK activation may be different depending on types of stimuli, cell types, and various p38 MAPK isoforms involved. Objective.—This review focuses on the recent advancement of the p38 MAPK isoforms as well as the roles of p38 MAPK in hematologic malignancies. Data Sources.—Review of pertinent published literature and work in our laboratory. Conclusions.—In some hematologic malignancies, activation of p38 plays a key role in promoting or inhibiting proliferation and also in increasing resistance to chemotherapeutic agents. The importance of different p38 isoforms in various cellular functions has been acknowledged recently. Further understanding of these isoforms will allow the design of more specific inhibitors to target particular isoforms to maximize the treatment effect and minimize the side effects for treating hematopoietic malignancies.

scholarly journals Biological Functions of HMGN Chromosomal Proteins

2020 ◽  
Vol 21 (2) ◽  
pp. 449
Author(s):  
Ravikanth Nanduri ◽  
Takashi Furusawa ◽  
Michael Bustin
Keyword(s):  
Biological Function ◽  
High Mobility ◽  
Cell Types ◽  
Vertebrate Development ◽  
Cellular Functions ◽  
Cell Identity ◽  
Multiple Cell ◽  
Cell Type Specific ◽  
Nucleosome Binding ◽  
Regulatory Sites

Chromatin plays a key role in regulating gene expression programs necessary for the orderly progress of development and for preventing changes in cell identity that can lead to disease. The high mobility group N (HMGN) is a family of nucleosome binding proteins that preferentially binds to chromatin regulatory sites including enhancers and promoters. HMGN proteins are ubiquitously expressed in all vertebrate cells potentially affecting chromatin function and epigenetic regulation in multiple cell types. Here, we review studies aimed at elucidating the biological function of HMGN proteins, focusing on their possible role in vertebrate development and the etiology of disease. The data indicate that changes in HMGN levels lead to cell type-specific phenotypes, suggesting that HMGN optimize epigenetic processes necessary for maintaining cell identity and for proper execution of specific cellular functions. This manuscript contains tables that can be used as a comprehensive resource for all the English written manuscripts describing research aimed at elucidating the biological function of the HMGN protein family.

scholarly journals Endometriosis and ovarian cancer risk

2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Javier de la Torre Fernández de Vega ◽  
Jose Luis Sánchez-Iglesias ◽  
Assumpt Perez-Benavente ◽  
Antonio Gil-Moreno ◽  
Rasheda Begum Dina ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clear Cell ◽  
Molecular Genetic ◽  
Cell Types ◽  
Ovarian Cancer Risk ◽  
New Paradigm ◽  
Ovarian Carcinomas ◽  
Genetic Studies ◽  
Ovarian Carcinogenesis ◽  
Increased Risk

Epithelial ovarian cancer presents different histological subtypes, mainly serous, mucinous, endometriod, clear cell, mixed and undifferentiated cell. Molecular genetic studies have led to a new paradigm based on a dualistic model of ovarian carcinogenesis. There is a causal association between endometriosis and specific types of ovarian carcinomas, but the magnitude of the risk is low and endometriosis is not considered a premalignant lesion. Among the endometriosis-associated ovarian tumors adenocarcinoma is the most common (Endometrioid and clear cell) (70%), sarcoma is the second most common malignancy (12%) and rare cell types 6%. The gynecologist should pay special attention to identify patients with endometriosis who may be at an increased risk for ovarian cancer.

scholarly journals A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types

2011 ◽  
Vol 438 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Stephen Jamieson ◽  
Jack U. Flanagan ◽  
Sharada Kolekar ◽  
Christina Buchanan ◽  
Jackie D. Kendall ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Tumour Growth ◽  
Insulin Signalling ◽  
Cell Types ◽  
Genetic Alterations ◽  
Growth Factor Signalling ◽  
Phosphoinositide 3 Kinase ◽  
Responsive Cell

Genetic alterations in PI3K (phosphoinositide 3-kinase) signalling are common in cancer and include deletions in PTEN (phosphatase and tensin homologue deleted on chromosome 10), amplifications of PIK3CA and mutations in two distinct regions of the PIK3CA gene. This suggests drugs targeting PI3K, and p110α in particular, might be useful in treating cancers. Broad-spectrum inhibition of PI3K is effective in preventing growth factor signalling and tumour growth, but suitable inhibitors of p110α have not been available to study the effects of inhibiting this isoform alone. In the present study we characterize a novel small molecule, A66, showing the S-enantiomer to be a highly specific and selective p110α inhibitor. Using molecular modelling and biochemical studies, we explain the basis of this selectivity. Using a panel of isoform-selective inhibitors, we show that insulin signalling to Akt/PKB (protein kinase B) is attenuated by the additive effects of inhibiting p110α/p110β/p110δ in all cell lines tested. However, inhibition of p110α alone was sufficient to block insulin signalling to Akt/PKB in certain cell lines. The responsive cell lines all harboured H1047R mutations in PIK3CA and have high levels of p110α and class-Ia PI3K activity. This may explain the increased sensitivity of these cells to p110α inhibitors. We assessed the activation of Akt/PKB and tumour growth in xenograft models and found that tumours derived from two of the responsive cell lines were also responsive to A66 in vivo. These results show that inhibition of p110α alone has the potential to block growth factor signalling and reduce growth in a subset of tumours.

scholarly journals Lymphocyte cell motility: the twisting, turning tale of phosphoinositide 3-kinase

2007 ◽  
Vol 35 (5) ◽  
pp. 1109-1113 ◽  
Author(s):  
J.S. Oak ◽  
M.P. Matheu ◽  
I. Parker ◽  
M.D. Cahalan ◽  
D.A. Fruman
Keyword(s):  
Cell Motility ◽  
Cell Types ◽  
Lymphocyte Migration ◽  
Regulatory Subunits ◽  
Lipid Kinases ◽  
Cell Type Specific ◽  
Phosphoinositide 3 Kinase ◽  
Lymphocyte Motility

The PI3K (phosphoinositide 3-kinase) family of lipid kinases regulate cell motility in diverse organisms and cell types. In mammals, the main PI3K enzyme activated by chemokine receptor signalling is the class IB isoform, p110γ. Studies of p110γ-knockout mice have shown an essential function for this isoform in chemotaxis of neutrophils and macrophages both in vitro and in vivo. However, the roles of p110γ and other PI3K enzymes and regulatory subunits in lymphocyte motility have been more difficult to discern. Recent studies of adoptively transferred, fluorescently labelled lymphocytes have revealed complex and unexpected functions for PI3K in lymphocyte migration in vivo. In this review we highlight cell-type-specific roles for PI3K catalytic and regulatory subunits in the homing and basal motility of lymphocytes in the intact lymph node.

scholarly journals Cell type-dependent control of p53 transcription and enhancer activity by p63

2018 ◽  
Author(s):  
Gizem Karsli Uzunbas ◽  
Faraz Ahmed ◽  
Morgan A. Sammons
Keyword(s):  
Transcriptional Activation ◽  
Cellular Response ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cell Type ◽  
P53 Family ◽  
Enhancer Activity ◽  
Response To Stress ◽  
Cell Type Specific ◽  
Stress Dependent

ABSTRACTTranscriptional activation by p53 provides powerful, organism-wide tumor suppression. In this work, we demonstrate that the p53-induced transcriptome varies based on cell type, reflects cell type-specific activities, and is considerably more broad than previously anticipated. This behavior is strongly influenced by p53 engagement with differentially active cell type-specific enhancers and promoters. In epithelial cell types, p53 activity is dependent on the p53 family member p63, which displays widespread enhancer binding. Notably, we demonstrate that p63 is required for epithelial enhancer identity including enhancers used by p53 during stress-dependent signaling. Loss of p63, but not p53, leads to site-specific depletion of enhancer-associated chromatin modifications, suggesting that p63 functions as an enhancer maintenance factor in epithelial cells. Additionally, a subset of epithelial-specific enhancers is dependent on the activity of p63 providing a direct link between lineage determination and enhancer structure. These data suggest a broad, cell-intrinsic mechanism for regulating the p53-dependent cellular response to stress through differential regulation ofcis-regulatory elements.

scholarly journals From 1D sequence to 3D chromatin dynamics and cellular functions: a phase separation perspective

2018 ◽  
Author(s):  
Sirui Liu ◽  
Ling Zhang ◽  
Hui Quan ◽  
Hao Tian ◽  
Luming Meng ◽  
...  
Keyword(s):  
Phase Separation ◽  
Chromatin Structure ◽  
Gc Content ◽  
Cell Types ◽  
Cell Type ◽  
Cellular Functions ◽  
Sequence Dependence ◽  
Chromatin Dynamics ◽  
Cell Type Specific ◽  
Different Cell Types

AbstractThe high-order chromatin structure plays a non-negligible role in gene regulation. However, the mechanism for the formation of different chromatin structures in different cells and the sequence dependence of this process remain to be elucidated. As the nucleotide distributions in human and mouse genomes are highly uneven, we identified CGI forest and prairie genomic domains based on CGI density, which better segregates genomic elements along the genome than GC content. The genome is then divided into two sequentially, epigenetically, and transcriptionally distinct regions. These two types of megabase-sized domains spatially segregate, but to a different extent in different cell types. Overall, the forests and prairies gradually segregate from each other in development, differentiation, and senescence. The multi-scale forest-prairie spatial intermingling is cell-type specific and increases in differentiation, thus helps define the cell identity. We propose that the phase separation of the 1D mosaic sequence in space, serving as a potential driving force, together with cell type specific epigenetic marks and transcription factors, shapes the chromatin structure in different cell types and renders them distinct genomic properties. The mosaicity of the genome manifested in terms of alternative forests and prairies of a species could be related to its biological processes such as differentiation, aging and body temperature control.

scholarly journals Correlation of p53 and DNA repair gene mutation patterns in human malignancies indicates different tumour suppression mechanisms of p53

2019 ◽  
Author(s):  
Xuemin Xue ◽  
Lin Dong ◽  
Liyan Xue ◽  
Yong-jie Lu
Keyword(s):  
Dna Repair ◽  
Gene Mutation ◽  
Human Cancer ◽  
Gene Mutations ◽  
Cell Types ◽  
Cellular Functions ◽  
Repair Gene ◽  
Human Cancers ◽  
Dna Repair Gene ◽  
Cancer Types

AbstractP53 suppresses tumorigenesis through multiple cellular functions/mechanisms. Recently, Janic A, et al. reported that DNA repair pathways are critical mediators of p53-dependent tumor suppression. We showed, by mining cBioPortal data of a range of human cancers, that the tendency of ‘mutual exclusivity’ of mutations in p53 and DNA repair genes only exist in very limited human cancer types. In the majority of human cancers, p53 mutations are equally distributed between DNA repair gene mutation positive and negative cases and in a number of human cancers, p53 and DNA repair gene mutations have a tendency of co-occurrence. These different correlation patterns of p53 and DNA repair gene mutations in human malignancies may reflect different critical molecular/cellular pathways activated by p53 in different organs or cell types to suppress tumorigenesis.

scholarly journals A Knockout Mouse Approach Reveals that TCTP Functions as an Essential Factor for Cell Proliferation and Survival in a Tissue- or Cell Type–specific Manner

2007 ◽  
Vol 18 (7) ◽  
pp. 2525-2532 ◽  
Author(s):  
Sung Ho Chen ◽  
Peih-Shan Wu ◽  
Chiang-Hung Chou ◽  
Yu-Ting Yan ◽  
Hsuan Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Types ◽  
Cell Type ◽  
Cellular Functions ◽  
Embryonic Fibroblasts ◽  
Embryonic Tissues ◽  
Targeted Gene Disruption ◽  
Specific Manner ◽  
Cell Type Specific ◽  
And Control

Translationally controlled Tumor Protein (TCTP) is an evolutionally highly conserved protein which has been implicated in many cellular functions that are related to cell growth, death, and even the allergic response of the host. To address the physiological roles of TCTP, we generated TCTP knockout mice by targeted gene disruption. Heterozygous mutants appeared to be developmentally normal. However, homozygous mutants (TCTP−/−) were embryonic lethal. TCTP−/− embryos were smaller in size than the control littermates at all postimplantation stages examined. Although TCTP is widely expressed in both extraembryonic and embryonic tissues, the most prominent defect of the TCTP−/− embryo at embryonic stage day 5.5 (E5.5) was in its epiblast, which had a reduced number of cells compared with wild-type controls. The knockout embryos also suffered a higher incidence of apoptosis in epiblast starting about E6.5 and subsequently died around E9.5–10.5 with a severely disorganized structure. Last, we demonstrated that TCTP−/− and control mouse embryonic fibroblasts manifested similar proliferation activities and apoptotic sensitivities to various death stimuli. Taken together, our results suggest that despite that TCTP is widely expressed in many tissues or cell types, it appears to regulate cell proliferation and survival in a tissue- or cell type–specific manner.

scholarly journals Glucocorticoid receptor collaborates with pioneer factors and AP-1 to execute genome-wide regulation

2021 ◽  
Author(s):  
Erin M Wissink ◽  
Delsy M. Martinez ◽  
Kirk T. Ehmsen ◽  
Keith R. Yamamoto ◽  
John T Lis
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Glucocorticoid Receptor ◽  
Human Cancer ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cell Type ◽  
Glucocorticoid Treatment ◽  
Cell Type Specific ◽  
Pioneer Factors

The glucocorticoid receptor (GR) regulates transcription through binding to specific DNA motifs, particularly at enhancers. While the motif to which it binds is constant across cell types, GR has cell type-specific binding at genomic loci, resulting in regulation of different genes. The presence of other bound transcription factors (TFs) is hypothesized to strongly influence where GR binds. Here, we addressed the roles of other TFs in the glucocorticoid response by comparing changes in GR binding and nascent transcription at promoters and distal candidate cis-regulatory elements (CCREs) in two distinct human cancer cell types. We found that after glucocorticoid treatment, GR binds to thousands of genomic loci that are primarily outside of promoter regions and are potentially enhancers. The majority of these GR binding sites are cell-type specific, and they are associated with pioneer factor binding. A small fraction of GR occupied regions (GORs) displayed increased bidirectional nascent transcription, which is a characteristic of many active enhancers, after glucocorticoid treatment. Non-promoter GORs with increased transcription were specifically enriched for AP-1 binding prior to glucocorticoid treatment. These results support a model of transcriptional regulation in which multiple classes of TFs are required. The pioneer factors increase chromatin accessibility, facilitating the binding of GR and additional factors. AP-1 binding poises a fraction of accessible sites to be rapidly transcribed upon glucocorticoid-induced GR binding. The coordinated activity of multiple TFs then results in cell type-specific changes in gene expression. We anticipate that many models of inducible gene expression also require multiple distinct TFs that act at multiple steps of transcriptional regulation.

Sign in / Sign up

Export Citation Format

Share Document