scholarly journals Essential Dosage-Dependent Functions of the Transcription Factor Yin Yang 1 in Late Embryonic Development and Cell Cycle Progression

2006 ◽  
Vol 26 (9) ◽  
pp. 3565-3581 ◽  
Author(s):  
El Bachir Affar ◽  
Frédérique Gay ◽  
Yujiang Shi ◽  
Huifei Liu ◽  
Maite Huarte ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Eukaryotic Cell ◽  
Dependent Manner ◽  
Phenotypic Analysis ◽  
Yin Yang 1 ◽  
Yin Yang

ABSTRACT Constitutive ablation of the Yin Yang 1 (YY1) transcription factor in mice results in peri-implantation lethality. In this study, we used homologous recombination to generate knockout mice carrying yy1 alleles expressing various amounts of YY1. Phenotypic analysis of yy1 mutant embryos expressing ∼75%, ∼50%, and ∼25% of the normal complement of YY1 identified a dosage-dependent requirement for YY1 during late embryogenesis. Indeed, reduction of YY1 levels impairs embryonic growth and viability in a dose-dependent manner. Analysis of the corresponding mouse embryonic fibroblast cells also revealed a tight correlation between YY1 dosage and cell proliferation, with a complete ablation of YY1 inducing cytokinesis failure and cell cycle arrest. Consistently, RNA interference-mediated inhibition of YY1 in HeLa cells prevents cytokinesis, causes proliferative arrest, and increases cellular sensitivity to various apoptotic agents. Genome-wide expression profiling identified a plethora of YY1 target genes that have been implicated in cell growth, proliferation, cytokinesis, apoptosis, development, and differentiation, suggesting that YY1 coordinates multiple essential biological processes through a complex transcriptional network. These data not only shed new light on the molecular basis for YY1 developmental roles and cellular functions, but also provide insight into the general mechanisms controlling eukaryotic cell proliferation, apoptosis, and differentiation.

scholarly journals The Olive Leaves Extract Has Anti-Tumor Effects against Neuroblastoma through Inhibition of Cell Proliferation and Induction of Apoptosis

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2178
Author(s):  
Fabio Morandi ◽  
Veronica Bensa ◽  
Enzo Calarco ◽  
Fabio Pastorino ◽  
Patrizia Perri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Cell Cycle Progression ◽  
Treatment Strategies ◽  
Annexin V ◽  
Dependent Manner ◽  
Induction Of Apoptosis ◽  
Dose Dependent

Neuroblastoma (NB) is the most common extra-cranial solid tumor of pediatric age. The prognosis for high-risk NB patients remains poor, and new treatment strategies are desirable. The olive leaf extract (OLE) is constituted by phenolic compounds, whose health beneficial effects were reported. Here, the anti-tumor effects of OLE were investigated in vitro on a panel of NB cell lines in terms of (i) reduction of cell viability; (ii) inhibition of cell proliferation through cell cycle arrest; (iii) induction of apoptosis; and (iv) inhibition of cell migration. Furthermore, cytotoxicity experiments, by combining OLE with the chemotherapeutic topotecan, were also performed. OLE reduced the cell viability of NB cells in a time- and dose-dependent manner in 2D and 3D models. NB cells exposed to OLE underwent inhibition of cell proliferation, which was characterized by an arrest of the cell cycle progression in G0/G1 phase and by the accumulation of cells in the sub-G0 phase, which is peculiar of apoptotic death. This was confirmed by a dose-dependent increase of Annexin V+ cells (peculiar of apoptosis) and upregulation of caspases 3 and 7 protein levels. Moreover, OLE inhibited the migration of NB cells. Finally, the anti-tumor efficacy of the chemotherapeutic topotecan, in terms of cell viability reduction, was greatly enhanced by its combination with OLE. In conclusion, OLE has anti-tumor activity against NB by inhibiting cell proliferation and migration and by inducing apoptosis.

scholarly journals Lamina-associated polypeptide 2α regulates cell cycle progression and differentiation via the retinoblastoma–E2F pathway

2006 ◽  
Vol 173 (1) ◽  
pp. 83-93 ◽  
Author(s):  
Daniela Dorner ◽  
Sylvia Vlcek ◽  
Nicole Foeger ◽  
Andreas Gajewski ◽  
Christian Makolm ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Serum Starvation ◽  
Dependent Manner ◽  
Cycle Progression ◽  
Promoter Sequences ◽  
Delayed Entry ◽  
Accelerated Proliferation

Lamina-associated polypeptide (LAP) 2α is a nonmembrane-bound LAP2 isoform that forms complexes with nucleoplasmic A-type lamins. In this study, we show that the overexpression of LAP2α in fibroblasts reduced proliferation and delayed entry into the cell cycle from a G0 arrest. In contrast, stable down-regulation of LAP2α by RNA interference accelerated proliferation and interfered with cell cycle exit upon serum starvation. The LAP2α-linked cell cycle phenotype is mediated by the retinoblastoma (Rb) protein because the LAP2α COOH terminus directly bound Rb, and overexpressed LAP2α inhibited E2F/Rb-dependent reporter gene activity in G1 phase in an Rb-dependent manner. Furthermore, LAP2α associated with promoter sequences in endogenous E2F/Rb-dependent target genes in vivo and negatively affected their expression. In addition, the expression of LAP2α in proliferating preadipocytes caused the accumulation of hypophosphorylated Rb, which is reminiscent of noncycling cells, and initiated partial differentiation into adipocytes. The effects of LAP2α on cell cycle progression and differentiation may be highly relevant for the cell- and tissue-specific phenotypes observed in laminopathic diseases.

scholarly journals Gfi1 Upregulates c-Myc Expression and Promotes c-Myc-Driven Cell Proliferation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3769-3769
Author(s):  
Yangyang Zhang ◽  
Fan Dong
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Transcriptional Repression ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Protein Levels ◽  
Enhanced Expression ◽  
Ubiquitin Proteasome

Gfi1 is a zinc-finger transcriptional repressor that plays an important role in hematopoiesis. When aberrantly activated, Gfi1 may function as a weak oncoprotein in the lymphoid system, but collaborate strongly with c-Myc in lymphomagenesis. c-Myc is a transcription factor that is frequently activated in human cancers including leukemia and lymphoma mainly due to its overexpression as a result of gene amplifications and chromosomal translocations. c-Myc overexpression may also result from stabilization of c-Myc protein, which is highly unstable and rapidly degraded through the ubiquitin-proteasome pathway. The mechanism by which Gfi1 collaborates with c-Myc in lymphomagenesis is incompletely understood. c-Myc activates gene expression by forming a heterodimeric complex with the partner protein Max, but may also repress target genes through interaction with transcription factor Miz-1. We previously showed that Gfi1 indirectly interacts with c-Myc through Miz-1 and collaborates with c-Myc to repress CDK inhibitors p21Cip1 and p15Ink4B. In this study, we show that Gfi1 augmented the level of c-Myc protein transiently expressed in Hela cells and the levels of MycER fusion protein stably expressed in the mouse pro-B Ba/F3 and myeloid 32D cells. The C-terminal ZF domains of Gfi1, but not its transcriptional repression and DNA binding activities, were required for c-Myc upregulation. Notably, although Miz-1 has been shown to stabilize c-Myc protein, the expression of c-Myc V394D mutant, which is defective in Miz-1 interaction, was still upregulated by Gfi1, suggesting that Gfi1-mediated c-Myc upregulation was independent of Miz-1 interaction. We further show that Gfi1 overexpression led to reduced polyubiquitination and increased stability of c-Myc protein. Interestingly, the levels of endogenous c-Myc mRNA and protein were augmented upon induction of Gfi1 expression in Ba/F3 and Burkitt lymphoma Ramos cells transduced with the doxycycline-inducible Gfi1 lentiviral construct, but reduced in Gfi1-knocked down human leukemic HL60 and U937 cells. Additionally, targeted deletion of Gfi1 resulted in reduced c-Myc expression in mouse lineage negative bone marrow cells, which was associated with a decline in the expression of c-Myc-activated target genes. The oncogenic potential of Myc derives from its ability to stimulate cell proliferation. Our results demonstrate that inducible expression of Gfi1 in Ba/F3 cells expressing MycER promoted Myc-driven cell cycle progression and proliferation. Thus, in addition to its role in c-Myc-mediated transcriptional repression, Gfi1 upregulates c-Myc expression at both mRNA and protein levels, leading to enhanced expression of c-Myc-activated genes and augmented cell proliferation driven by c-Myc. Together, these data may reveal a novel mechanism by which Gfi1 collaborates with c-Myc in lymphomagenesis. Disclosures No relevant conflicts of interest to declare.

Expression, Role in Transformation and Prognostic Significance of the Transcription Factor Yin Yang 1 (YY1) in Non-Hodgkin’s Lymphoma: Analyses in NHL Tissues by Experimental and Bioinformatic Approaches

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2827-2827
Author(s):  
Massimo Libra ◽  
Giancarlo Castellano ◽  
Stavroula Baritaki ◽  
Sara Huerta-Yepez ◽  
Giovanni Ligresti ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
B Cells ◽  
Cell Lines ◽  
Gene Transcription ◽  
High Grade ◽  
Data Set ◽  
Expression Levels ◽  
Yin Yang 1 ◽  
Yin Yang

Abstract Objective and Rationale Non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with variable patterns of behavior and responses to treatment. Although at present a significant number of high grade lymphoma patients can be cured with intensive regimens of cytotoxic and immunotherapeutic drugs, still these patients may relapse or become resistant to treatment. Therefore, there is a need to identify novel factors involved in lymphoma development and progression and hopefully to be used as targeted therapies. Thus, the objective of the present study was to explore the potential involvement of Yin Yang 1 (YY1) in the development as well as in the prognosis of NHL. Hypothesis Our previous studies showed that YY1 is overexpressed in several human cancer cell lines and its expression correlates with resistance to chemo- immune-mediated apoptosis. Prognostic and diagnostic significance of YY1 has been recently shown in prostate cancer. Thus, we hypothesized that YY1 overexpression in NHL may be involved in transformation and act as a prognostic biomarker. Methods and Designs Overexpression of YY1 has been shown by western blot and RT-PCR in NHL cell lines compared to normal B-cells. Validation of in vitro results has been performed by immunohistochemistry (IHC) and bioinformatics in NHL tissues. IHC analyses were performed in two commercial NHL tissue arrays containing 104 samples. Results Gene expression analysis and association with clinical features of the transcription factor YY1 were evaluated using three different datasets of publicly available microarray data from lymphoma tumor-biopsy specimens. By analyzing the data set (221 NHL and 25 normal B-cells) by Basso et al., (Nat Genet 37:382, 2005) higher YY1 transcript levels were found in lymphoma tissues (BL and DLBCL) in comparison to normal B-cells. No significant differences were found with the other lymphoma histotypes. This class comparison analysis revealed that YY1 could be involved in the transformation of B cells giving rise to high-grade lymphomas. Expression levels of YY1 were analyzed in association with the available main clinical and biological parameters using the expression data of two different high grade lymphoma studies with a total of approximately 400 samples (Rosenwald et al., N Engl J Med.346:1937, 2002; Hummel et al., N Engl J Med.354:2419, 2006). Upregulated expression of YY1 was found in the subgroups of patients with positive proliferation signature scores with respect to those with negative proliferation signature scores. A significant correlation was found between BCL6, post-germinal center (GC) marker and YY1 expression. The presence of BCL6 protein in the tumors is associated with high levels of YY1 gene transcription. These data confirm that YY1 is mostly overexpressed among high-grade lymphomas that usually are post-GC transit. Survival analysis in both datasets reveal that higher levels of YY1 gene transcription are associated with poor outcome. Finally, biological network analysis, using the Proprietary Ingenuity Pathway analysis software, was performed to better understand the biological significance of these findings. Among all genes present in the data set by Hummel et al. (2006) a significant positive correlation with YY1 expression was found in 374 genes. In this data set, Top Networks Functions associated with YY1 expression levels were cellular movement, cell morphology, cell cycle, and cell-to-cell adhesion. These analyses indicate the potential direct involvement of YY1 in the regulation of cell cycle pathways and in the regulation of cellular motility. Conclusions and Implications Overall, the findings reveal that YY1 is involved in lymphoma development and may be useful as a biomarker of NHL transformation as well as a potential target for therapeutic interventions.

scholarly journals VprBP/DCAF1 Regulates the Degradation and Nonproteolytic Activation of the Cell Cycle Transcription Factor FoxM1

2017 ◽  
Vol 37 (13) ◽  
Author(s):  
Xianxi Wang ◽  
Anthony Arceci ◽  
Kelly Bird ◽  
Christine A. Mills ◽  
Rajarshi Choudhury ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Chromosome Instability ◽  
Vital Role ◽  
Activation Mechanism ◽  
Cycle Progression ◽  
Protein Levels ◽  
Ubiquitin System

ABSTRACT The oncogenic transcription factor FoxM1 plays a vital role in cell cycle progression, is activated in numerous human malignancies, and is linked to chromosome instability. We characterize here a cullin 4-based E3 ubiquitin ligase and its substrate receptor, VprBP/DCAF1 (CRL4VprBP), which we show regulate FoxM1 ubiquitylation and degradation. Paradoxically, we also found that the substrate receptor VprBP is a potent FoxM1 activator. VprBP depletion reduces expression of FoxM1 target genes and impairs mitotic entry, whereas ectopic VprBP expression strongly activates a FoxM1 transcriptional reporter. VprBP binding to CRL4 is reduced during mitosis, and our data suggest that VprBP activation of FoxM1 is ligase independent. This implies a nonproteolytic activation mechanism that is reminiscent of, yet distinct from, the ubiquitin-dependent transactivation of the oncoprotein Myc by other E3s. Significantly, VprBP protein levels were upregulated in high-grade serous ovarian patient tumors, where the FoxM1 signature is amplified. These data suggest that FoxM1 abundance and activity are controlled by VprBP and highlight the functional repurposing of E3 ligase substrate receptors independent of the ubiquitin system.

scholarly journals Protein Kinase SGK Mediates Survival Signals by Phosphorylating the Forkhead Transcription Factor FKHRL1 (FOXO3a)

2001 ◽  
Vol 21 (3) ◽  
pp. 952-965 ◽  
Author(s):  
Anne Brunet ◽  
Jongsun Park ◽  
Hien Tran ◽  
Linda S. Hu ◽  
Brian A. Hemmings ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Survival ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Cellular Functions ◽  
Forkhead Transcription Factor ◽  
Pi3k Activation ◽  
Phosphoinositide 3 Kinase

ABSTRACT Serum- and glucocorticoid-inducible kinases (SGKs) form a novel family of serine/threonine kinases that are activated in response to a variety of extracellular stimuli. SGKs are related to Akt (also called PKB), a serine/threonine kinase that plays a crucial role in promoting cell survival. Like Akt, SGKs are activated by the phosphoinositide-3 kinase (PI3K) and translocate to the nucleus upon growth factor stimulation. However the physiological substrates and cellular functions of SGKs remained to be identified. We hypothesized that SGKs regulate cellular functions in concert with Akt by phosphorylating common targets within the nucleus. The best-characterized nuclear substrates of Akt are transcription factors of the Forkhead family. Akt phosphorylates Forkhead transcription factors such as FKHRL1, leading to FKHRL1's exit from the nucleus and the consequent shutoff of FKHRL1 target genes. We show here that SGK1, like Akt, promotes cell survival and that it does so in part by phosphorylating and inactivating FKHRL1. However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. These findings indicate that SGK acts in concert with Akt to propagate the effects of PI3K activation within the nucleus and to mediate the biological outputs of PI3K signaling, including cell survival and cell cycle progression.

scholarly journals Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Proliferation

2016 ◽  
Vol 36 (19) ◽  
pp. 2487-2502 ◽  
Author(s):  
Shakur Mohibi ◽  
Shashank Srivastava ◽  
Aditya Bele ◽  
Sameer Mirza ◽  
Hamid Band ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Histone Acetylation ◽  
Cell Cycle Progression ◽  
Site Directed Mutagenesis ◽  
Dependent Manner ◽  
Cycle Progression ◽  
Functional Roles ◽  
A Cell ◽  
Cycle Dependent

Alteration/deficiency in activation 3 (ADA3) is an essential component of specific histone acetyltransferase (HAT) complexes. We have previously shown that ADA3 is required for establishing global histone acetylation patterns and for normal cell cycle progression (S. Mohibi et al., J Biol Chem 287:29442–29456, 2012,http://dx.doi.org/10.1074/jbc.M112.378901). Here, we report that these functional roles of ADA3 require its acetylation. We show that ADA3 acetylation, which is dynamically regulated in a cell cycle-dependent manner, reflects a balance of coordinated actions of its associated HATs, GCN5, PCAF, and p300, and a new partner that we define, the deacetylase SIRT1. We use mass spectrometry and site-directed mutagenesis to identify major sites of ADA3 acetylated by GCN5 and p300. Acetylation-defective mutants are capable of interacting with HATs and other components of HAT complexes but are deficient in their ability to restore ADA3-dependent global or locus-specific histone acetylation marks and cell proliferation inAda3-deleted murine embryonic fibroblasts (MEFs). Given the key importance of ADA3-containing HAT complexes in the regulation of various biological processes, including the cell cycle, our study presents a novel mechanism to regulate the function of these complexes through dynamic ADA3 acetylation.

scholarly journals SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation

2011 ◽  
Vol 192 (1) ◽  
pp. 43-54 ◽  
Author(s):  
Stine Jørgensen ◽  
Morten Eskildsen ◽  
Kasper Fugger ◽  
Lisbeth Hansen ◽  
Marie Sofie Yoo Larsen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligase ◽  
Cell Cycle Progression ◽  
Control Cell ◽  
Ubiquitin Proteasome System ◽  
Eukaryotic Cell ◽  
S Phase ◽  
Nuclear Antigen ◽  
Dependent Manner ◽  
Histone H4

The eukaryotic cell cycle is regulated by multiple ubiquitin-mediated events, such as the timely destruction of cyclins and replication licensing factors. The histone H4 methyltransferase SET8 (Pr-Set7) is required for chromosome compaction in mitosis and for maintenance of genome integrity. In this study, we show that SET8 is targeted for degradation during S phase by the CRL4(CDT2) ubiquitin ligase in a proliferating cell nuclear antigen (PCNA)–dependent manner. SET8 degradation requires a conserved degron responsible for its interaction with PCNA and recruitment to chromatin where ubiquitylation occurs. Efficient degradation of SET8 at the onset of S phase is required for the regulation of chromatin compaction status and cell cycle progression. Moreover, the turnover of SET8 is accelerated after ultraviolet irradiation dependent on the CRL4(CDT2) ubiquitin ligase and PCNA. Removal of SET8 supports the modulation of chromatin structure after DNA damage. These results demonstrate a novel regulatory mechanism, linking for the first time the ubiquitin–proteasome system with rapid degradation of a histone methyltransferase to control cell proliferation.

scholarly journals The Oncogenic Function of PLAGL2 is Mediated via Specific Target Genes Through a Wnt-independent Mechanism in Colorectal Cancer

2020 ◽  
Author(s):  
Anthony D. Fischer ◽  
Daniel A. Veronese-Paniagua ◽  
Shriya Swaminathan ◽  
Hajime Kashima ◽  
Deborah C. Rubin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Bhlh Transcription Factor ◽  
Cycle Progression

ABSTRACTColorectal cancer (CRC) tumorigenesis and progression are linked to common oncogenic mutations, especially in the tumor suppressor APC, whose loss triggers the deregulation of TCF4/β-Catenin activity. CRC tumorigenesis is also driven by multiple epi-mutational modifiers, such as transcriptional regulators. We describe the common (and near-universal) activation of the zinc finger transcription factor and Let-7 target PLAGL2 in CRC and find that it is a key driver of intestinal epithelial transformation. PLAGL2 drives proliferation, cell cycle progression, and anchorage-independent growth in CRC cell lines and non-transformed intestinal cells. Investigating effects of PLAGL2 on downstream pathways revealed very modest effects on canonical Wnt signaling. Alternatively, we find pronounced effects on the direct PLAGL2 target genes IGF2, a fetal growth factor, and ASCL2, an intestinal stem cell-specific bHLH transcription factor. Inactivation of PLAGL2 in CRC cell lines has pronounced effects on ASCL2 reporter activity. Furthermore, ASCL2 expression can partially rescue deficits of proliferation and cell cycle progression caused by depletion of PLAGL2 in CRC cell lines. Thus, the oncogenic effects of PLAGL2 appear to be mediated via core stem cell and onco-fetal pathways, with minimal effects on downstream Wnt signaling.

Sign in / Sign up

Export Citation Format

Share Document