scholarly journals One Function—Multiple Mechanisms: The Manifold Activities of p53 as a Transcriptional Repressor

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Levin Böhlig ◽  
Karen Rother
Keyword(s):  
Tumor Suppressor ◽  
Target Genes ◽  
Transcriptional Repressor ◽  
Underlying Mechanism ◽  
Transcriptional Level ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Functional Inactivation ◽  
Tumor Suppressive Function ◽  
Transcription Factor P53

Maintenance of genome integrity is a dynamic process involving complex regulation systems. Defects in one or more of these pathways could result in cancer. The most important tumor-suppressor is the transcription factor p53, and its functional inactivation is frequently observed in many tumor types. The tumor suppressive function of p53 is mainly attributed to its ability to regulate numerous target genes at the transcriptional level. While the mechanism of transcriptional induction by p53 is well characterized, p53-dependent repression is not understood in detail. Here, we review the manifold mechanisms of p53 as a transcriptional repressor. We classify two different categories of repressed genes based on the underlying mechanism, and novel mechanisms which involve regulation through noncoding RNAs are discussed. The complete elucidation of p53 functions is important for our understanding of its tumor-suppressor activity and, therefore, represents the key for the development of novel therapeutic approaches.

Restoring Ikaros Function in Leukemia : Casein Kinase II ( CK2) Inhibition Restores Ikaros Tumor Supressor Function and Shows Theraputic Efficacy in Preclinical Models of High Risk Pediatric Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3712-3712
Author(s):  
Chandrika S. Gowda ◽  
Chunhua Song ◽  
Sunil Muthusami ◽  
Yali Ding ◽  
Mansi Sachdev ◽  
...  
Keyword(s):  
Cell Cycle ◽  
High Risk ◽  
Tumor Suppressor ◽  
Target Genes ◽  
Transcriptional Repressor ◽  
Casein Kinase Ii ◽  
Casein Kinase ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity

Abstract One common feature of high-risk pediatric B-cell acute lymphoblastic leukemia (B-ALL) is impaired function of the Ikaros (IKZF1) tumor suppressor gene. Ikaros encodes a DNA-binding, zinc finger protein that regulates expression of its target genes. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-SEQ) we determined that Ikaros targets multiple genes that regulate cell cycle progression. Functional studies provided evidence that Ikaros acts as a transcriptional repressor of several key cell cycle-promoting genes. We hypothesize that Ikaros’ ability to regulate transcription is reduced in leukemia and that restoration of Ikaros function as transcriptional repressor of cell cycle-promoting genes will have a strong anti-leukemia effect. We have previously shown that Casein Kinase II (CK2) directly phosphorylates Ikaros in vivo and that this phosphorylation impairs Ikaros function. Here, we show that the activity of Casein Kinase II (CK2) is more than 5-fold increased in primary B-ALL cells as compared to normal bone marrow in kinase assays. We tested whether CK2 inhibition can enhance the binding of Ikaros to cell cycle-promoting genes and enhance Ikaros transcriptional repressor activity. Treatment of leukemia cell lines, as well as primary B-ALL cells, with different CK2 inhibitors resulted in enhanced Ikaros binding to its target genes, as evidenced by quantitative chromatin immunoprecipitation (qChIP). This was associated with transcriptional repression of the Ikaros target genes that function as cell cycle promoters, as evidenced by quantitative real-time PCR (qRT-PCR), and by cell cycle arrest in treated cells. CK2 inhibition had a particularly pronounced effect on Ikaros activity in cells of primary high-risk B-ALL, which carry a deletion of one Ikaros allele. When these cells were untreated Ikaros was unable to bind promoters of its target genes. CK2 inhibition restored Ikaros binding to promoters of the cell cycle-promoting genes resulting in their repression. These results suggest that CK2 inhibition has an anti-proliferative effect on leukemia cells and that these effects occur via enhanced Ikaros tumor suppressor activity as a transcriptional repressor of cell cycle-promoting genes. We tested whether CK2 inhibition can produce an anti-leukemia effect in vivo using two preclinical human-mouse xenograft models of B-ALL: Nalm6 xenografts and primary patient-derived xenografts produced from high-risk leukemia cells that have a deletion of one Ikaros allele. Our results demonstrate that CK2 inhibition results in a potent anti-leukemia therapeutic effect in both xenograft models as evidenced by a reduction of leukemia burden in bone marrow and in spleen of treated mice, along with their prolonged survival as compared to controls. In summary, our results demonstrate the therapeutic efficacy of a novel therapeutic approach for high-risk leukemia – restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trial for high-risk leukemia, including cases with deletion of one Ikaros allele. Supported by the National Institutes of Health R01 HL095120, and the Four Diamonds Fund Endowment. Disclosures No relevant conflicts of interest to declare.

scholarly journals RB Family Tumor Suppressor Activity May Not Relate to Active Silencing of E2F Target Genes

2014 ◽  
Vol 74 (18) ◽  
pp. 5266-5276 ◽  
Author(s):  
Tinke L. Vormer ◽  
Kamila Wojciechowicz ◽  
Marleen Dekker ◽  
Sandra de Vries ◽  
Anja van der Wal ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Target Genes ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity

scholarly journals Serine 15 Phosphorylation of p53 Directs Its Interaction with B56γ and the Tumor Suppressor Activity of B56γ-Specific Protein Phosphatase 2A

2007 ◽  
Vol 28 (1) ◽  
pp. 448-456 ◽  
Author(s):  
Geoffrey P. Shouse ◽  
Xin Cai ◽  
Xuan Liu
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Specific Protein ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Phosphatase 2A ◽  
Tumor Suppressive Function

ABSTRACT Earlier studies have demonstrated a functional link between B56γ-specific protein phosphatase 2A (B56γ-PP2A) and p53 tumor suppressor activity. Upon DNA damage, a complex including B56γ-PP2A and p53 is formed which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21, and the inhibition of cell proliferation. Although an enhanced interaction between p53 and B56γ is observed after DNA damage, the underlying mechanism and its significance in PP2A tumor-suppressive function remain unclear. In this study, we show that the increased interaction between B56γ and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. In addition, we demonstrate that the B56γ3-induced inhibition of cell proliferation, induction of cell cycle arrest in G1, and blockage of anchorage-independent growth are also dependent on Ser15 phosphorylation of p53 and p53-B56γ interaction. Taken together, our results provide a mechanistic link between Ser15 phosphorylation-mediated p53-B56γ interaction and the modulation of p53 tumor suppressor activity by PP2A. We also show an important link between ATM activity and the tumor-suppressive function of B56γ-PP2A.

Targeting the p53 tumor suppressor activity in glioblastomas using small molecule MDM2-inhibitor

2011 ◽  
Vol 42 (01) ◽  
Author(s):  
P. Monfared ◽  
T. Viel ◽  
G. Schneider ◽  
Y. Waerzeggers ◽  
S. Rapic ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Small Molecule ◽  
Suppressor Activity ◽  
P53 Tumor Suppressor ◽  
Tumor Suppressor Activity ◽  
Mdm2 Inhibitor

Merlin cooperates with neurofibromin and Spred1 to suppress the Ras–Erk pathway

2020 ◽  
Author(s):  
Yan Cui ◽  
Lin Ma ◽  
Stephan Schacke ◽  
Jiani C Yin ◽  
Yi-Ping Hsueh ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Binding Sites ◽  
Neurofibromatosis Type ◽  
Kinase Domain ◽  
Erk Pathway ◽  
Suppressor Activity ◽  
The Third ◽  
Tumor Suppressor Activity ◽  
Multiple Signaling

Abstract The Ras–Erk pathway is frequently over-activated in human tumors. Neurofibromatosis type 1 and 2 (NF1, NF2) are characterized by multiple tumors of Schwann cell origin. The NF1 tumor suppressor neurofibromin is a principal Ras-GAP accelerating Ras inactivation, whereas the NF2 tumor suppressor merlin is a scaffold protein coordinating multiple signaling pathways. We have previously reported that merlin interacts with Ras and p120RasGAP. Here, we show that merlin can also interact with the neurofibromin/Spred1 complex via merlin-binding sites present on both proteins. Further, merlin can directly bind to the Ras-binding domain and the kinase domain of Raf1. As the third component of the neurofibromin/Spred1 complex, merlin cannot increase the Ras-GAP activity; rather, it blocks Ras binding to Raf1 by functioning as a ‘selective Ras barrier’. Merlin-deficient Schwann cells require the Ras–Erk pathway activity for proliferation. Accordingly, suppression of the Ras–Erk pathway likely contributes to merlin’s tumor suppressor activity. Taken together, our results, and studies by others, support targeting or co-targeting of this pathway as a therapy for NF2 inactivation-related tumors.

scholarly journals JunB Breakdown in Mid-/Late G2 Is Required for Down-Regulation of Cyclin A2 Levels and Proper Mitosis

2008 ◽  
Vol 28 (12) ◽  
pp. 4173-4187 ◽  
Author(s):  
Rosa Farràs ◽  
Véronique Baldin ◽  
Sandra Gallach ◽  
Claire Acquaviva ◽  
Guillaume Bossis ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Genetic Instability ◽  
S Phase ◽  
Subsequent Reduction ◽  
Suppressor Activity ◽  
Cell Synchronization ◽  
Tumor Suppressor Activity ◽  
A Cell ◽  
Cyclin A2

ABSTRACT JunB, a member of the AP-1 family of dimeric transcription factors, is best known as a cell proliferation inhibitor, a senescence inducer, and a tumor suppressor, although it also has been attributed a cell division-promoting activity. Its effects on the cell cycle have been studied mostly in G1 and S phases, whereas its role in G2 and M phases still is elusive. Using cell synchronization experiments, we show that JunB levels, which are high in S phase, drop during mid- to late G2 phase due to accelerated phosphorylation-dependent degradation by the proteasome. The forced expression of an ectopic JunB protein in late G2 phase indicates that JunB decay is necessary for the subsequent reduction of cyclin A2 levels in prometaphase, the latter event being essential for proper mitosis. Consistently, abnormal JunB expression in late G2 phase entails a variety of mitotic defects. As these aberrations may cause genetic instability, our findings contrast with the acknowledged tumor suppressor activity of JunB and reveal a mechanism by which the deregulation of JunB might contribute to tumorigenesis.

scholarly journals Protein Phosphatase 2A Regulatory Subunit B56α Associates with c-Myc and Negatively Regulates c-Myc Accumulation

2006 ◽  
Vol 26 (7) ◽  
pp. 2832-2844 ◽  
Author(s):  
Hugh K. Arnold ◽  
Rosalie C. Sears
Keyword(s):  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Cell Function ◽  
Cell Transformation ◽  
Protein Phosphatase 2A ◽  
Regulatory Subunit ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Structural Subunit ◽  
Phosphatase 2A

ABSTRACT Protein phosphatase 2A (PP2A) plays a prominent role in controlling accumulation of the proto-oncoprotein c-Myc. PP2A mediates its effects on c-Myc by dephosphorylating a conserved residue that normally stabilizes c-Myc, and in this way, PP2A enhances c-Myc ubiquitin-mediated degradation. Stringent regulation of c-Myc levels is essential for normal cell function, as c-Myc overexpression can lead to cell transformation. Conversely, PP2A has tumor suppressor activity. Uncovering relevant PP2A holoenzymes for a particular target has been limited by the fact that cellular PP2A represents a large heterogeneous population of trimeric holoenzymes, composed of a conserved catalytic subunit and a structural subunit along with a variable regulatory subunit which directs the holoenzyme to a specific target. We now report the identification of a specific PP2A regulatory subunit, B56α, that selectively associates with the N terminus of c-Myc. B56α directs intact PP2A holoenzymes to c-Myc, resulting in a dramatic reduction in c-Myc levels. Inhibition of PP2A-B56α holoenzymes, using small hairpin RNA to knock down B56α, results in c-Myc overexpression, elevated levels of c-Myc serine 62 phosphorylation, and increased c-Myc function. These results uncover a new protein involved in regulating c-Myc expression and reveal a critical interconnection between a potent oncoprotein, c-Myc, and a well-documented tumor suppressor, PP2A.

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