Sequence-Specific Talens-Induced DLEU1 Gene Disruption Significantly Suppresses Apoptosis and Increases Phosphorylation Of AKT and Ikba In Pediatric Burkitt Lymphoma (PBL): DLEU1 May Act As a Tumor Suppressor Gene In PBL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1279-1279
Author(s):  
Sanghoon Lee ◽  
Changhong Yin ◽  
Timmy O'Connell ◽  
Janet Ayello ◽  
Carmella van de Ven ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Mrna Expression ◽  
Tumor Suppressor Gene ◽  
Gene Disruption ◽  
Caspase 3 ◽  
Suppressor Gene ◽  
Raji Cells ◽  
Mock Control ◽  
Apoptotic Genes

Abstract Background Pediatric Burkitt Lymphoma (BL) is the most common histological subtype of Non Hodgkin Lymphoma (NHL) in children and adolescents (Cairo et al, Blood, 2007; Miles/Cairo, BJHaem, 2012). We previously identified, in a subset analysis, that children with BL and a 13q deletion, particularly 13q14.3, had significantly poorer outcome and inferior overall survival (OS) despite aggressive short, intensive multi-agent chemotherapy (Poirel/Cairo et al, Leukemia, 2009; Nelson/Cairo/Sanger et al, BJHaem, 2009). Deleted in Lymphocytic Leukemia 1 (DLEU1) is a BL classifier gene on 13q14.3 region (Dave et al, NEJM, 2006). DLEU1 has been implicated in regulating programmed cell death in patients by inducing TUBB2C and UBR1 expression. Sequence-specific Transcription Activator-Like Effector Nucleases (TALENs) technologies have been developed for precision targeted genome editing in in vitro and in vivo experiments with high efficiency as a new experimental and therapeutic tool (Sander et al, Nat Bio, 2011). We have previously reported TALENs mediated transient downregulation of DLEU1 in Raji cells (Figure 1), and demonstrated a decrease in the spontaneous apoptotic rate and an increase in cell proliferation in transiently DLEU1 down-regulated Raji cells (Lee/Cairo et al, ASH, 2012). Objectives We hypothesize that DLEU1 may act as a tumor suppressor gene and therefore investigated whether the silencing of DLEU1 results in changes in proliferation, programmed cell death and associated signaling pathways induced by Rituximab and Cyclophosphamide alone and in combination in TALEN-mediated DLEU1 knockout Raji BL cells. Methods A stable, single DLEU1 knockout clone (DLEU1 KO) was isolated from Raji cells transfected with DLEU1 TALENs (Lee/Cairo et al, ASH, 2012). Genomic DNA and total RNA were extracted using a DNA extraction kit (Promega) and Trizol (Invitrogen) for verification of endogenous DLEU1 gene disruption by TALENs. qRT-PCR was performed by CFX96 (Bio-rad) and the protein level was measured by western blotting. DLEU1 KO cells were plated (1x104 cells) into 48 or 96 well plates and then treated with Rituximab (0, 1, 10 and 100ug/ml) and/or Cyclophosphamide (0, 1, 5 and 10mM) and cell proliferation and apoptosis were measured by MTS (Promega) and Caspase 3/7 (Promega) assay. Statistical significance was determined by a one tailed paired Student t-test. Results DLEU1 KO (mono-allelic deletion) in Raji (BL) exhibited significantly reduced DLEU1 mRNA expression compared to mock control cells (83% reduction, p<0.006). There was significantly reduced expression of c-myc, TUBB2C and UBR1 mRNA (85%, p<0.001; 60%, p<0.04; 25%, p<0.006), respectively in DLEU1 KO compared to mock control cells. DLEU1-KO showed significant reduction of Caspase 3/7 activities (25% at 24hrs, p<0.007; 33% at 48hrs, p<0.03) and significant increase in cell proliferation (20% at 24hrs, p<0.04; 25% at 48hrs, p<0.03). DLEU1-KO showed a significant increase in expression of anti-apoptotic genes, Bcl-2, Bcl-xL and Mcl-1 mRNA (14%, p<0.03; 30%, p<0.04; 17%, p<0.04), respectively and a significantly a decrease in mRNA expression of pro-apoptotic genes, Bax and Bad (18%, p<0.04; 14%, p<0.04), respectively. There was a significant increase in phosphorylation of IkBa (2.6 fold, p<0.007) and Akt (1.5 fold, p<0.05) in DLEU1 KO. There was a significant reduction in Caspase-dependent apoptosis with RTX (15% reduction, p<0.05), CTX alone (24% reduction, p<0.03), and in combination (35% reduction, p<0.03) in DLEU1-KO compared to mock control. A significant increase in cell proliferation was observed with RTX (10% increase, p<0.04), CTX alone (9.4% increase, p<0.05), and combination (7.7% increase, p<0.02) in DLEU1-KO. RTX treated DLEU1-KO showed a significant increase in expression in Bcl-2 and Bcl-xL mRNA (1.3 fold, p<0.05 and 2.0 fold, p<0.02), respectively and a significant decrease in mRNA expression of Bax (1.2 fold, p<0.03). Conclusions We demonstrate that 1) TALENs mediated DLEU1 gene knockout resulted in downregulation of DLEU1 mRNA and consequently, inhibition of BL apoptosis and increase in cell proliferation, through several mechanism(s), and 2) the silencing of DLEU1 resulted in decrease in apoptosis in RTX, CTX alone and in combination treatment. We hypothesize that deletion of DLEU1 in childhood BL may result in chemotherapy resistance secondarily to a loss of a tumor suppressor gene. Disclosures: No relevant conflicts of interest to declare.

Talens-Mediated DLEU1 Gene Silencing in Burkitt Lymphoma (BL): Implication of Lncrna DLEU1 Gene As a Potential Tumor Suppressor Gene in BL.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2403-2403
Author(s):  
Sanghoon Lee ◽  
Changhong Yin ◽  
Janet Ayello ◽  
Carmella van de Ven ◽  
Henry Hwang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Mrna Expression ◽  
Tumor Suppressor Gene ◽  
Burkitt Lymphoma ◽  
Genomic Dna ◽  
Caspase 3 ◽  
Suppressor Gene ◽  
Gene Modification ◽  
Raji Cells

Abstract Abstract 2403 Background: Pediatric Burkitt Lymphoma (BL) is the most common histological subtype of Non Hodgkin Lymphoma (NHL) in children and adolescents (Cairo et al., Blood, 2007; Miles/Cairo, BJHaem., 2012). We previously identified in a subset analysis that children with BL and a 13q deletion, particularly 13q14.3, had significantly poorer outcome and inferior overall survival (OS) despite aggressive short, intensive multiagent chemotherapy (Poirel/Cairo et al., Leukemia, 2009; Nelson/Cairo/Sanger et al., BJHaem., 2009). Deleted in Lymphocytic Leukemia 1 (DLEU1) is a long non codign RNA gene with the BL classifier genes as reported by Dave et al (NEJM. 2006) on chromosome 13q14.3 region and the expression levels of RASSF1, TUBB2C and UBR1 were significantly higher in BL than in diffuse large B-cell lymphoma (DLBCL) (Day/Cairo et al., AACR, 2008). Sequence-specific Zinc Finger Nucleases (ZFN) and Transcription Activator-Like Effector Nucleases (TALENs) technologies have been developed for precision targeted genome editing in in vitro experiments with high efficiency and TALEN technology has been applied in a variety of organisms and stem cells for new experimental and therapeutic tools (Carlson et al., Mol Ther., 2012). Objectives: We hypothesize that 1) TALEN technology is suitable for the modification of and silencing of DLEU1 locus and 2) DLEU1 may have function as a tumor suppressor gene and therefore examined whether the loss of DLEU1 by TALEN-mediated DLEU1 knockdown Raji BL cells result in change in proliferation and programmed cell death. Methods: TALENs were constructed based on REAL (restriction enzyme and ligation) assembly methods (Sander et al., Nat. Biotech, 2011) for DLEU1 gene modification. DLEU1 TALEN pairs or combinations were transfected into 293T and Raji cells using lipofectamin reagent (Invitrogen) and Amaxa nucleofection kit, respectively. Genomic DNA and total RNA were extracted using genomic DNA extraction kit (Promega) and Trizol reagent (Invitrogen). Surveyor mutation detection assay (Transgenomic) was applied for TALENs validities and confirmed by sequencing analysis. Quantitative RT-PCR was performed by CFX96 Real-time system (Bio-rad) using qScript™ cDNA Synthesis Kit (Quantas) and SsoFast™ EvaGreen® Supermix (Bio-rad). Transfected cells were re-plated (1×104) into 48 well plates at 24hours post transfection and then counted every 24hrs for cell proliferation assay. For spontaneous apoptosis assay, DLEU1 TALENs transfected Raji cells were re-plated into 96 well plates at 24hours post-transfection and measured caspase 3/7 activities (Promega) using Clarity Luminescence microplate reader (Biotek) and statistical significance was determined by a one or two-tailed Student t-test. Results: Three pairs of functional DLEU1 TALENs (T1, T2, and T3) targeting endogenous DLEU1 gene generated and confirmed their validities with gene modification caused by non-homologous end joining (NHEJ) in TALENs mediated 293T [Figure 1]. Forty eight hours after transiently transfection in Raji cells, combined DLEU1 TALENs, T1/T2 (T12), T1/T3 (T13) and T2/T3 (T23) mediated Raji cells were dramatically reduced expression of DLEU1 mRNA (about 82–93% reduction) compared to untransfected Raji cells [92% reduction (p<0.002), 93% (p<0.0006), and 92% (p<0.0003)], respectively, and compared to empty vector as a control [82% reduction (p<0.05), 87% (p<0.0001), and 82% (p<0.001, respectively)]. T12 and T13-mediated DLEU1 knockdown Raji cells showed significantly an increase of cell proliferation [1.2-fold (p<0.02) and 1.5-fold (p<0.04) at day 5, respectively]. In spontaneous apoptotic assays, T13 mediated Raji showed significantly 20% (p<0.05) of reduction of caspase 3/7 activities. In comparison of mRNA expression of DLEU1 network genes in T13 mediated Raji cells, there were no significant differences in mRNA expression of c-myc compared to control, however, there was significantly reduced expression of RASSF1 and UBR1 mRNA (<7.7-fold, p<0.005 and <11.1-fold, p<0.0005), respectively, and significantly increased expression of TUBB2C mRNA (>7.5-fold, p<0.005). Conclusions: We demonstrate that 1) DLEU1-TALENs are useful tools for the modification of endogenous DLEU1 gene expression, 2) DLEU1 may have as a tumor suppressor gene in BL, and 3) DLEU1 TALEN mediated gene knockdown resulted in inhibition of BL apoptosis and increase in cell proliferation. Disclosures: No relevant conflicts of interest to declare.

Overexpression Of Deleted In Lymphocytic Leukemia 1 (DLEU1) Significantly Induces Programmed Cell Death and Inhibits Cell Proliferation In Primary Mediastinal B-Cell Lymphoma (PMBL): DLEU1 May Be a Tumor Suppressor Gene In a Subset Of Patients With PMBL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3852-3852 ◽  
Author(s):  
Changhong Yin ◽  
Tae-Hoon Chung ◽  
Janet Ayello ◽  
Tae-Hyun Park ◽  
Carmella van de Ven ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
B Cell ◽  
Mrna Expression ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Suppressor Gene ◽  
Lymphocytic Leukemia ◽  
Mock Control

Abstract Background Primary Mediastinal large B-cell lymphoma (PMBL) is a rare form of Non Hodgkin Lymphoma (NHL) representing 2% of mature B-cell non-Hodgkin lymphoma in patients less than 18 years of age (Lones/Cairo et al., JCO, 2000; Burkhardt et al., BJH, 2005). PMBL has similar histo-pathological features along the biologic spectrum between Diffuse Large B-Cell Lymphoma (DLBCL) and classical HL (cHL) (Abramson et al., Blood, 2005). We have recently reported that a significantly decrease in EFS among children and adolescent PMBL patients compared with other stage III non-PMBL pediatric DLBCL patients following FAB/LMB96 therapy, suggesting that children and adolescent PMBL may be an inherently different B-NHL (Gerrard/Cairo et al., Blood, 2013). Nevertheless, the genetic mechanisms underlying the pathogenesis of PMBL remain unknown. Using high-resolution, microarray-based genomic techniques chromosomal losses at 13q14 was identified in 5 of the 37 (13%) PMBL tumor samples indicating localization of potential tumor suppressor genes at 13q that may be involved in the etiology of PMBL (Wessondorf, et al, Leuk., 2007). DLEU1 (Deleted in lymphocytic Leukemia 1) is a Burkitt lymphoma (BL) classifier gene (Dave et al., NEJM, 2006) and is located in the chromosome 13q14.3 region. DLEU1 interacts with 19 proteins including of c-Myc, RASSF1, TUBB2C and UBR1. DLEU1 has been implicated as a tumor suppressor in BL (Lee/Yin/Cairo et al., ASH, 2012) and in chronic lymphocytic leukemia (Garding et al., Plos Genet., 2013). Objectives We hypothesize that DLEU1 may act as a tumor suppressor gene through induction of caspase-3/7 activity thereby inhibiting cell proliferation and down-regulation of constitutively activated signaling pathways in PMBL. Methods The full length of cDNA encoding DLEU1 was fused into pEGFP-N3 vector and pEGFP-DLEU1fusion construct (Lee/Yin/Cairo et al., ASH, 2012) was transfected into Karpas-1106P cells using Amaxa Nucleofector kit, followed by the manufacturer’s instruction. Forty-eight hours post transient transfection, total RNA was extracted and 1ug of total RNA was used for cDNA synthesized as above. For comparison of mRNA expression of network genes, quantitative RT-PCR was performed by CFX96 Real-time (Bio-rad). The expression of DLEU1 protein in DLEU1 transient transfected Karpas-1106P cells was confirmed both by western blotting analysis and under fluorescent microscope. In brief, the total lysates was prepared from DELU1 transfected cells at 48hours post-transfection, and membrane was hybridized with Rabbit polyclonal DLEU1 antibody (ProteinTech) on immune blotting. MTS (Promega) and Caspase 3/7 assay (Promega) were employed to examine the effects on cell proliferation and apoptosis. Statistical significance was determined by one tailed paired Student t-test. Results The expression of DLEU1 mRNA in DLEU1 transiently transfected Karpas-1106P (DLEU1-Karpas) cells was significantly higher than empty vector alone transfected cell as mock control (78-fold increase, p<0.01). Comparing mRNA expression of DLEU1 network genes in DLEU1-Karpas cells to mock control cells, we observed a significant decrease in mRNA expression of the anti-apoptotic gene, Bcl-xL (73% reduction, p<0.01) and suppressors of cell signaling genes, SOCS1 and SOCS3 (52% reduction, p<0.05 and 44% reduction, p<0.01, respectively). There was a significant reduction in the mRNA expression of oncogenes, Pim-1 and c-Myc (72% reduction, p<0.04 and 54% reduction, p<0.03) respectively, in DLEU1-Karpas cells compared to mock control cells. Cell proliferation was significantly inhibited 18% (p<0.03) whereas Caspase 3/7 activity was significantly increased 1.5-fold (p<0.03) in DLEU1-Karpas cells at 48hours post transfection. Lastly, we found significant decreases of protein expression in phoshpho-Akt (67% reduction, p<0.01), phoshpho-ikBa (48% reduction, p<0.02), phoshpho-STAT3 (15% reduction, p<0.02) and c-Myc (25% reduction, p<0.01), respectively in DLEU1-Karpas cells. Conclusions We demonstrated that transient overexpression of DLEU1 1) significantly inhibits cell proliferation and induces programmed cell death, and 2) downregulates constitutively activated signaling pathways in PMBL, and therefore, DLEU1 may in part act as a tumor suppressor gene in a subset of patients with PMBL. Disclosures: No relevant conflicts of interest to declare.

Overexpression of Deleted Lymphocytic Leukemia 1 (DLEU1) Inhibits Proliferation of Burkitt Lymphoma (BL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2654-2654
Author(s):  
Sanghoon Lee ◽  
Changhong Yin ◽  
Janet Ayello ◽  
Carmella van de Ven ◽  
Charles Biggar ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Mrna Expression ◽  
Tumor Suppressor Gene ◽  
Burkitt Lymphoma ◽  
Suppressor Gene ◽  
Lymphocytic Leukemia ◽  
Full Length ◽  
Raji Cells ◽  
Total Rna

Abstract Abstract 2654 Background: Burkitt Lymphoma (BL) represents approximately 40% of all childhood and adolescents Non Hodgkin Lymphoma (Cairo et al., Blood, 2007; Miles/Cairo, BJHaem., 2012), and pediatric BL patients with chromosome del13q14.3 region had significantly poorer outcome and inferior overall survival despite aggressive short, intensive multiagent chemotherapy in subset analysis (Poirel/Cairo et al., Leukemia, 2009; Nelson/Cairo/Sanger et al., BJHaem., 2009). Deleted in Lymphocytic Leukemia 1 (DLEU1) is often deleted in B-CLL patients (Liu et al., Oncogene, 1997; Wolf et al., Hum. Mol. Genet., 2001) with the BL classifier genes (Dave et al., NEJM. 2006) on chromosome 13q14.3 region, is recognized to interact with Tubulin beta 2C (TUBB2C), RASSF1A, and E3 ubiquitin-protein ligase (UBR1), and p53 and their mRNA expression levels were significantly higher in BL than in diffuse large B-cell lymphoma (DLBCL) (Day/Cairo et al., AACR, 2008). DLEU1 may have function as a tumor suppressor gene, however, functions and mechanisms underlying DLEU1 expression in the cells are poorly understood. OBJECTIVE: We propose that DLEU1 may act as a tumor suppressor gene and sought out to examine whether gains of overexpression of DLEU1 in embryonic kidney cells and Burkitt Lymphoma cells result in inhibition of tumor proliferation METHODS: In order to get a full length of DLEU1 cDNA, total RNA was prepared from embryonic kidney epithelial 293T and Raji Burkitt lymphoma cells using Trizol (Invitrogen), and cDNA was synthesized by qScript™ cDNA Synthesis Kit (Quantas). The full length of cDNA encoding DLEU1 was fused into pEGFP-N3 vector. pEGFP-DLEU1fusion construct was transfected into 293T and Raji cells using lipofectamin or Amaxa Nucleofector™ kit V, respectively, followed by the manufacturer's instruction. Twenty-four (293T) or Forty-eight hours (Raji) post transiently transfection, total RNA was extracted and 1ug of total RNA was used for cDNA synthesized as above. For comparison of mRNA expression of network genes, quantitative RT-PCR was performed using SsoFast™ EvaGreen® Supermix reagent by CFX96 Real-time system (Bio-rad) and statistical significance was performed by one-tailed Student t-test. For observation of expression of DLEU1 fusion protein, GFP only as control and GFP-DLEU1 transiently overexpressed 293T and Raji cells were observed under fluorescent microscope, and total lysates were prepared from both cells at 24 hours (293T) and 48hours (Raji) post-transfection and were hybridized with Rabbit polyclonal DLEU1 anitbody (Proteintech) on immune blotting. For cell proliferation assay, GFP-DLEU1 transiently overexpressed 293T and Raji cells were re-plated at 24hours post-transfection, and then counted every 24hrs. RESULTS: DLEU1 full length cDNA (234nt, 78amino acid) successfully fused into pEGFP expression vector and observed GFP fluorescence under fluorescent microscope in both 293T and Raji cells, and the predicted size of the fusion protein was confirmed by western blot (approximately 36kDa) [Figure 1]. The level of DLEU1 mRNA expression in GFP-DLEU1 transiently transfected 293T and Raji cells was significantly higher than GFP only transfected Raji cell as control [50% increase (p<0.05) and 25% increase (p<0.005), respectively]. In comparison of mRNA expression of DLEU1 network genes in DLEU1 overexpressed 293T cells, there were no significant differences in mRNA expression of c-myc compared to control, however, there was significantly increased expression of RASSF1 and UBR1 mRNA (>1.5-fold, p<0.03 and >1.2-fold, p<0.02), respectively, and significantly reduced expression of TUBB2C mRNA (<1.2-fold, p<0.03) in DLEU1 overexpressed 293T cells. In addition, in DLEU1 overexpressed Raji cells, there was no significant differences in c-myc mRNA similar to 293T cells, however, there was significantly increased expression of UBR1 mRNA (>1.1-fold, p<0.05), and significantly reduced expression of RASSF1 and TUBB2C mRNA (<1.4-fold, p<0.02 and <1.5-fold, p<0.03) in DLEU1 overexpressed Raji cells. DLEU1 transiently overexpressed cells showed an inhibition of cell proliferation in both 293T and Raji cells [60% reduction (p<0.05) at day 4 and 20% reduction (p<0.01) at day 5, respectively]. CONCLUSION: These results suggest that DLEU1 may act as a tumor suppressor gene and that following overexpression of DLEU1 resulted in inhibition of cell proliferation in Burkitt Lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals GIPC2 is an endocrine-specific tumor suppressor gene for both sporadic and hereditary tumors of RET- and SDHB-, but not VHL-associated clusters of pheochromocytoma/paraganglioma

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Yeqing Dong ◽  
Yongsheng Huang ◽  
Chengyan Fan ◽  
Liang Wang ◽  
Ran Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Chromaffin Cells ◽  
Disease Free Survival ◽  
Suppressor Gene ◽  
Adrenal Chromaffin Cell ◽  
Putative Tumor Suppressor Gene ◽  
Mutant Effect ◽  
Hereditary Tumors

AbstractPheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET, VHL, and SDHB, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET-mutated tumors almost always occur in the adrenal while SDHB-mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2, a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27, suppressed MAPK/ERK and HIF-1ɑ pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.

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