Structure of putative tumor suppressor ALDH1L1.
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ABSTRACT:
SUBMITTER: Tsybovsky Y
PROVIDER: S-EPMC8748788 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundFragile Histidine Triad protein (FHIT), as a known tumor suppressor protein, has been proposed to play crucial role in inhibiting p53 degradation by MDM2. Studies have confirmed FHIT interaction with p53 or MDM2, although functional interacting domains of FHIT with MDM2 and/or p53 are not completely defined. Thus, through determining the significant structural interacting domains of FHIT, information with regard to MDM2 and p53 would be provided. As there were no previous studies evaluating the interaction of optimized important parts of target molecules, docking study was employed.MethodsTruncated structures of FHIT were screened to reveal critical sections engaging in FHIT interaction. HEX program was used in order to study the interaction of target structures.ResultsGiven the total energy, FHIT structures (β5-7, α1) and (α1) of FHIT were showed to be better candidates in comparison with other structures in interaction with optimized MDM2 part. Furthermore, FHIT structures (β4-7, α1) and (β5-7, α1) were considered to be better than other structures in interaction with optimized p53 part. FHIT truncates which interact with MDM2 optimized part exhibited lower energy levels than FHIT truncates which interact with p53 optimized part.ConclusionOur results can be useful for designing new inhibitors of this protein complex interaction which would result in tumor repression.
| S-EPMC4009097 | biostudies-literature
Project description:Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) is commonly downregulated in human cancers through promoter methylation. We proposed that ALDH1L1 loss promotes malignant tumor growth. Here, we investigated the effect of the Aldh1l1 mouse knockout (Aldh1l1-/-) on hepatocellular carcinoma using a chemical carcinogenesis model. Fifteen-day-old male Aldh1l1 knockout mice and their wild-type littermate controls (Aldh1l1+/+) were injected intraperitoneally with 20 μg/g body weight of DEN (diethylnitrosamine). Mice were sacrificed 10, 20, 28, and 36 weeks post-DEN injection, and livers were examined for tumor multiplicity and size. We observed that while tumor multiplicity did not differ between Aldh1l1-/- and Aldh1l1+/+ animals, larger tumors grew in Aldh1l1-/- compared to Aldh1l1+/+ mice at 28 and 36 weeks. Profound differences between Aldh1l1-/- and Aldh1l1+/+ mice in the expression of inflammation-related genes were seen at 10 and 20 weeks. Of note, large tumors from wild-type mice showed a strong decrease of ALDH1L1 protein at 36 weeks. Metabolomic analysis of liver tissues at 20 weeks showed stronger differences in Aldh1l1+/+ versus Aldh1l1-/- metabotypes than at 10 weeks, which underscores metabolic pathways that respond to DEN in an ALDH1L1-dependent manner. Our study indicates that Aldh1l1 knockout promoted liver tumor growth without affecting tumor initiation or multiplicity.
| S-EPMC8268287 | biostudies-literature
Project description:Folate (vitamin B9) is a common name for a group of coenzymes that function as carriers of chemical moieties called one-carbon groups in numerous biochemical reactions. The combination of these folate-dependent reactions constitutes one-carbon metabolism, the name synonymous to folate metabolism. Folate coenzymes and associated metabolic pathways are vital for cellular homeostasis due to their key roles in nucleic acid biosynthesis, DNA repair, methylation processes, amino acid biogenesis, and energy balance. Folate is an essential nutrient because humans are unable to synthesize this coenzyme and must obtain it from the diet. Insufficient folate intake can ultimately increase risk of certain diseases, most notably neural tube defects. More than 20 enzymes are known to participate in folate metabolism. Single-nucleotide polymorphisms (SNPs) in genes encoding for folate enzymes are associated with altered metabolism, changes in DNA methylation and modified risk for the development of human pathologies including cardiovascular diseases, birth defects, and cancer. ALDH1L1, one of the folate-metabolizing enzymes, serves a regulatory function in folate metabolism restricting the flux of one-carbon groups through biosynthetic processes. Numerous studies have established that ALDH1L1 is often silenced or strongly down-regulated in cancers. The loss of ALDH1L1 protein positively correlates with the occurrence of malignant tumors and tumor aggressiveness, hence the enzyme is viewed as a candidate tumor suppressor. ALDH1L1 has much higher frequency of non-synonymous exonic SNPs than most other genes for folate enzymes. Common SNPs at the polymorphic loci rs3796191, rs2886059, rs9282691, rs2276724, rs1127717, and rs4646750 in ALDH1L1 exons characterize more than 97% of Europeans while additional common variants are found in other ethnic populations. The effects of these SNPs on the enzyme is not clear but studies indicate that some coding and non-coding ALDH1L1 SNPs are associated with altered risk of certain cancer types and it is also likely that specific haplotypes define the metabolic response to dietary folate. This review discusses the role of ALDH1L1 in folate metabolism and etiology of diseases with the focus on non-synonymous coding ALDH1L1 SNPs and their effects on the enzyme structure/function, metabolic role and association with cancer.
| S-EPMC6831610 | biostudies-literature
Project description:The TrkC neurotrophin receptor belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase receptor and therefore generally considered to be a proto-oncogene. We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Furthermore, reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation, as well as in vivo tumor growth. Finally, we provide evidence that a mutation of TrkC detected in a sporadic cancer is a loss-of-proapoptotic function mutation. Together, these data support the conclusion that TrkC is a colorectal cancer tumor suppressor.
| S-EPMC3581924 | biostudies-literature
Project description:A lambda gt11 cDNA library of chicken embryo fibroblasts was screened with biotinylated Jun protein to identify Jun-binding clones. Eight such clones were isolated; one contains a gene referred to as jif-1 that is homologous to the putative tumor suppressor gene QM. jif-1 codes for a protein of 25 kDa that binds to the leucine zipper of viral and cellular Jun. The Jif-1 protein also binds to itself. Jif-1 does not contain a leucine zipper, and it does not bind to the 12-O-tetradecanoylphorbol 13-acetate response element DNA sequence. Complex formation of Jif-1 with Jun inhibits DNA binding and reduces transactivation by Jun. Addition of Fos protein to Jun-Jif-1 complexes restores DNA-binding activity. These observations suggest that Jif-1 is a negative regulator of Jun.
| S-EPMC47005 | biostudies-other
Project description:BRCA1, a multi-domain protein, is mutated in a large percentage of hereditary breast and ovarian cancers. BRCA1 is most often mutated in three domains or regions: the N-terminal RING domain, exons 11-13, and the BRCT domain. The BRCA1 RING domain is responsible for the E3 ubiquitin ligase activity of BRCA1 and mediates interactions between BRCA1 and other proteins. BRCA1 ubiquitinates several proteins with various functions. The BRCA1 BRCT domain binds to phosphoproteins with specific sequences recognized by both BRCA1 and ATM/ATR kinases. Structural studies of the RING and BRCT domains have revealed the molecular basis by which cancer causing mutations impact the functions of BRCA1. While no structural data is available for the amino acids encoded by exons 11-13, multiple binding sites and functional domains exist in this region. Many mutations in exons 11-13 have deleterious effects on the function of these domains. In this mini-review, we examine the structure-function relationships of the BRCA1 protein and the relevance to cancer progression.
| S-EPMC3380633 | biostudies-literature
Project description:We previously reported the identification of TUSC1 (Tumor Suppressor Candidate 1), as a novel intronless gene isolated from a region of homozygous deletion at D9S126 on chromosome 9p in human lung cancer. In this study, we examine the differential expression of TUSC1 in human lung cancer cell lines by western blot and in a primary human lung cancer tissue microarray by immunohistochemical analysis. We also tested the functional activities and mechanisms of TUSC1 as a tumor suppressor gene through growth suppression in vitro and in vivo. The results showed no expression of TUSC1 in TUSC1 homozygously deleted cells and diminished expression in some tumor cell lines without TUSC1 deletion. Interestingly, the results from a primary human lung cancer tissue microarray suggested that higher expression of TUSC1 was correlated with increased survival times for lung cancer patients. Our data demonstrated that growth curves of tumor cell lines transfected with TUSC1 grew slower in vitro than those transfected with the empty vector. More importantly, xenograph tumors in nude mice grew significantly slower in vivo in cells stably transfected with TUSC1 than those transfected with empty vector. In addition, results from confocal microscopy and immunohistochemical analyses show distribution of TUSC1 in the cytoplasm and nucleus in tumor cell lines and in normal and tumor cells in the lung cancer tissue microarray. Taken together, our results support TUSC1 has tumor suppressor activity as a candidate tumor suppressor gene located on chromosome 9p.
| S-EPMC3679066 | biostudies-literature
Project description:The transcription factor E2A is essential for lymphocyte development. In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sézary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the protooncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells after restoration of E2A expression, we identify several E2A-regulated genes that interfere with oncogenic signaling pathways, including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity.
| S-EPMC3149217 | biostudies-literature
Project description:Members of the leucine zipper putative tumor suppressor (LZTS) family play crucial roles in transcription modulation and cell cycle control. We previously demonstrated that LZTS2 functions as a novel ?-catenin-interacting protein and represses ?-catenin-mediated transcription on T-cell factor/lymphoid enhancing factor. Here, we investigate the biological role of LZTS2 using newly established Lzts2 KO mice. Homozygosity for loss-of-function of the Lzts2-targeted allele resulted in severe kidney and urinary tract developmental defects, including renal/ureteral duplication, hydroureter, and hydronephrosis, which were visible prenatally. Altered ureteric bud outgrowth was identified in Lzts2 null embryos. Further analysis indicated that ?-catenin subcellular localization was altered in fibroblasts isolated from Lzts2 null embryos. In addition, Wnt growth factor-induced ?-catenin-mediated transcriptional activity was increased in Lzts2 null fibroblasts, suggesting a direct role for Lzts2 in the Wnt signaling pathway. These data demonstrate a critical role of LZTS2 in renal development and implicate LZTS2 as a critical regulator of ?-catenin-mediated nephrogenesis.
| S-EPMC3220563 | biostudies-literature
Project description:Background: CAP-Gly domain containing linker protein family member 4 (CLIP4) plays an important role in cancers. However, its expression, prognostic value, and biological effect in breast cancer remain unclear. Methods: Data on patients diagnosed with breast cancer were retrieved from the TCGA-BRCA and other public omics databases. The expression profile of CLIP4 was analyzed using Oncomine, bc-GenExMiner, and TCGA. The prognostic value of CLIP4 was determined by Kaplan-Meier Plotter and Human Protein Atlas. Identification of genes co-expressed with CLIP4 and potential mechanism analyses were performed using UALCAN, STRING, Metascape, and GSEA. The epigenetic characteristics of CLIP4 were determined by DiseaseMeth and MEXPRESS. Results: CLIP4 was downregulated and its expression was negatively correlated with estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor type 2 (HER2) status, Nottingham prognostic index (NPI), and Scarff-Bloom-Richardson (SBR) grade in breast cancer, whereas it was positively linked to basal-like and triple negative breast cancer status. Ectopic expression of CLIP4 was related with poor prognosis. In the analysis of genes co-expressed with CLIP4, GSEA showed that the Hedgehog (Hh), JAK-STAT, ERBB, Wnt signaling pathway, cell adhesion molecules, and pathways in cancer were dissimilarly enriched in the CLIP4 expression high phenotype. Analysis of the genetics and epigenetics of CLIP4 indicated that its expression was negatively correlated with DNA methylation. Conclusion: Methylated CLIP4 may be a novel prognostic and therapeutic biomarker for breast cancer.
| S-EPMC7870488 | biostudies-literature