YPEL3

Last updated
YPEL3
Identifiers
Aliases YPEL3 , yippee like 3
External IDs OMIM: 609724 MGI: 1913340 HomoloGene: 116010 GeneCards: YPEL3
Orthologs
SpeciesHumanMouse
Entrez

83719

66090

Ensembl

ENSG00000090238

ENSMUSG00000042675

UniProt

P61236

P61237

RefSeq (mRNA)

NM_001145524
NM_031477

NM_025347
NM_026875

RefSeq (protein)

NP_001138996
NP_113665

Location (UCSC) Chr 16: 30.09 – 30.1 Mb Chr 7: 126.78 – 126.78 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Yippee-like 3 (Drosophila) is a protein that in humans is encoded by the YPEL3 gene. [5] [6] YPEL3 has growth inhibitory effects in normal and tumor cell lines. [7] One of five family members (YPEL1-5), YPEL3 was named in reference to its Drosophila melanogaster orthologue. [6] Initially discovered in a gene expression profiling assay of p53 activated MCF7 cells, [8] induction of YPEL3 has been shown to trigger permanent growth arrest or cellular senescence in certain human normal and tumor cell types. [7] DNA methylation of a CpG island near the YPEL3 promoter as well as histone acetylation may represent possible epigenetic mechanisms leading to decreased gene expression in human tumors. [7]

Contents

Gene location and protein structure

Human YPEL3 is located on the short arm of chromosome 16 (p1611.2) and covers 4.62kb from 30015754 to 30011130 on the reverse strand. [6] [9] The Drosophila Yippee protein was identified as a putative zinc finger motif containing protein exhibiting a high degree of conservation among the cysteines and histidines. [10] Zinc fingers function as structural platforms for DNA binding.

Nomenclature

YPEL3 was first identified as murine SUAP, named for small unstable apoptotic protein because of its apparent role in cellular growth inhibition via apoptosis when studied in myeloid precursor cell lines . [11] SUAP later attained its current designation as YPEL3 (Yippee like three), after it was discovered to be one of five human genes possessing homology with the Drosophila Yippee protein. [6]

Discovery

The Drosophila Yippee protein was originally discovered in a yeast interaction trap screen when it was found to physically interact with Hyalophora cecropia Hemolin. After subsequent cloning and sequencing experiments Yippee was found to be a conserved gene family of proteins present in a diverse range of eukaryotic organisms, ranging from fungi to humans. [10] When analyzed at the amino acid level, Drosophila melanogaster Yippee and YPEL1 displayed a high level of homology (76%). During later sequence analysis of human chromosome 22, researchers identified a gene family YPEL1-YPEL5, which had high homology with the Drosophila Yippee gene. [6]

YPEL3’s role as a novel tumor suppressor and its involvement in cellular proliferation were discovered during experiments to investigate p53 dependent cell cycle arrest. While investigating the p53 tumor suppressor protein, microarray studies which targeted Hdmx and Hdm2, both p53 negative regulators, revealed YPEL3 as a potential p53 regulated gene in MCF7 breast cancer cells. [8] Investigation into its function led to the discovery of YPEL3 being a novel protein whose growth suppressive activity is thought to be mediated through a cellular senescence pathway. [7]

Function

Regulation by p53

p53 is a tumor suppressor protein encoded by the human gene TP53 whose function is to prevent unregulated cell growth. p53 can be activated in response to a wide variety of cellular stressors, both oncogenic and non-oncogenic. An important checkpoint in a complex pathway, activated p53 has been shown to bind DNA and transcriptionally regulate genes that can mediate a variety of cellular growth processes including DNA repair, growth arrest, cellular senescence and apoptosis. [12] The importance of functioning p53 in the regulation of the cell cycle is evident in that 55% of human cancers exhibit p53 mutations. [13]

YPEL3 was discovered to be a possible p53 target after a screen for such genes was performed in MCF7 breast cancer cells following RNAi knockdown of p53 negative inhibitors. [8] In both human normal and tumor cell lines, YPEL3 has been shown to be a p53-inducible gene. Two putative p53 binding sites have been identified, one 1.3-Kbp 5' of the YPEL3 promoter and another upstream of the YPEL3 promoter. [6]

Cellular senescence

As a part of the p53 pathway response and its anti-proliferation role, cellular senescence has gained attention for its working relationship with tumor suppressor genes. [14] Characterized by the limited ability of cultured normal cells to divide, senescence has been shown to be triggered through oncogenic activation( premature senescence) as well as telomere shortening as the result of successive rounds of DNA replication (replicative senescence). [15] Recognized hallmarks of cellular senescence include senescence associated(SA)beta galactosidase staining and the appearance of senescence-associated heterochromatic foci(SAHF) within the nuclei of senescent cells. [16] [17]

Although studies in murine myeloid precursor cell lines indicated YPEL3 to have a role in apoptosis, human YPEL3 failed to demonstrate an apoptotic response using sub-G1 or poly ADP ribose polymerase cleavage as accepted indicators of programmed cell death. [11] YPEL3 has been shown to trigger premature senescence when studied in IMR90 primary human fibroblasts. Studies in U2OS osteosarcoma cells and MCF7 breast cancer cells have also demonstrated increased cellular senescence upon YPEL3 induction. [7] As further possible evidence to its function, reduced expression of YPEL3 has been observed in ovarian, lung, and colon tumor cell lines. [7] [18]

Epigenetic modification

Epigenetics is the study of changes in gene activity that do not involve alterations to genetic code, or DNA. Instead, just above the genome sits various epigenetic markers which serve to provide instructions to activate or inactivate genes to varying degrees. This silencing or activation of genes has been recognized to play an important role in the differentiation of nascent cells and several human disease states including cancer. Unlike genetic mutations, epigenetic changes are considered reversible, although further study is needed.

Two common methods of epigenetic modification are DNA methylation and histone modification. Specifically, hypermethylation of CpG islands( guanine and cytosine rich spans of DNA) near the promoters of tumor suppressor genes have been documented in specific tumor cell lines. In the case of the tumor suppressors VHL (associated with von Hippel–Lindau disease), p16, hMLH1, and BRCA1(a gene associated with breast cancer susceptibility), hypermethylation of the CpG-island has been shown to be a method of gene inactivation. [19]

Both histone acetylation and DNA methylation have been studied as possible epigenetic means of regulating YPEL3 expression. When studied in Cp70 ovarian carcinoma cells, hypermethylation of a CpG island immediately upstream of the YPEL3 promoter has been seen to down regulate YPEL3 expression. [7] Hypermethylation seen in the promoters of tumor suppressor genes are cancer type specific, allowing each tumor type to be identifiable with an individual pattern. [20] Such discoveries have led researchers to investigate epigenetic markers as potential diagnostic tools, prognostic factors, and indicators for the responsiveness to treatment of human cancers, although continued study is needed. [19]

Related Research Articles

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encodes its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">ATM serine/threonine kinase</span>

ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, oxidative stress, topoisomerase cleavage complexes, splicing intermediates, R-loops and in some cases by single-strand DNA breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor suppressors.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

p16 Mammalian protein found in Homo sapiens

p16, is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor. It is encoded by the CDKN2A gene. A deletion in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in many types of cancer.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">RASSF1</span> Protein-coding gene in the species Homo sapiens

Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene.

<span class="mw-page-title-main">Secreted frizzled-related protein 1</span> Protein-coding gene in the species Homo sapiens

Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.

<span class="mw-page-title-main">DLC1</span> Protein-coding gene in the species Homo sapiens

Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene.

<span class="mw-page-title-main">HIC1</span> Protein-coding gene in the species Homo sapiens

Hypermethylated in cancer 1 protein is a protein that in humans is encoded by the HIC1 gene.

<span class="mw-page-title-main">CDKN2A</span> Protein-coding gene in the species Homo sapiens

CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family member p16 and p14arf. Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">LATS2</span> Protein-coding gene in the species Homo sapiens

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miR-137

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<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

<span class="mw-page-title-main">DIRAS3 (gene)</span> Mammalian protein found in Homo sapiens

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Epigenetics of physical exercise is the study of epigenetic modifications to the cell genome resulting from physical exercise. Environmental factors, including physical exercise, have been shown to have a beneficial influence on epigenetic modifications. Generally, it has been shown that acute and long-term exercise has a significant effect on DNA methylation, an important aspect of epigenetic modifications.

Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.

DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the promoter hypermethylation where the CPGs islands in the promoter regions are methylated contributing or causing genes to be silenced.

CpG island hypermethylation is a phenomenon that is important for the regulation of gene expression in cancer cells, as an epigenetic control aberration responsible for gene inactivation. Hypermethylation of CpG islands has been described in almost every type of tumor.

Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000090238 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000042675 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: Yippee-like 3 (Drosophila)" . Retrieved 2014-08-16.
  6. 1 2 3 4 5 6 Hosono K, Sasaki T, Minoshima S, Shimizu N (2008). "Identification and characterization of a novel gene family YPEL in a wide spectrum of eukaryotic species". Gene. 340 (1): 31–43. doi:10.1016/j.gene.2004.06.014. PMID   15556292.
  7. 1 2 3 4 5 6 7 Kelley KD, Miller KR, Todd A, Kelley AR, Tuttle R, Berberich SJ (2010). "YPEL3, a p53-Regulated Gene that Induces Cellular Senescence". Cancer Research. 70 (9): 3566–75. doi:10.1158/0008-5472.CAN-09-3219. PMC   2862112 . PMID   20388804.
  8. 1 2 3 Heminger K, Markey M, Mpagi M, Berberich SJ (2009). "Alterations in gene expression and sensitivity to genotoxic stress following HdmX or Hdm2 knockdown in human tumor cells harboring wild-type p53". Aging. 1 (1): 89–108. doi:10.18632/aging.100008. PMC   2783638 . PMID   19946469.
  9. ↑ "AceView: Gene:YPEL3, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView".
  10. 1 2 Roxström-Lindquist K, Faye I (2001). "The Drosophila gene Yippee reveals a novel family of putative zinc binding proteins highly conserved among eukaryotes". Insect Molecular Biology. 10 (1): 77–86. doi:10.1046/j.1365-2583.2001.00239.x. PMID   11240639. S2CID   46559510.
  11. 1 2 Baker SJ (2003). "Small unstable apoptotic protein, an apoptosis-associated protein, suppresses proliferation of myeloid cells". Cancer Research. 63 (3): 705–12. PMID   12566317.
  12. ↑ Levine AJ, Oren M (2009). "The first 30 years of p53: growing ever more complex". Nature Reviews Cancer. 9 (10): 749–58. doi:10.1038/nrc2723. PMC   2771725 . PMID   19776744.
  13. ↑ Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991). "P53 mutations in human cancers". Science. 253 (5015): 49–53. Bibcode:1991Sci...253...49H. doi:10.1126/science.1905840. PMID   1905840. S2CID   38527914.
  14. ↑ Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007). "Restoration of p53 function leads to tumour regression in vivo". Nature. 445 (7128): 661–5. doi:10.1038/nature05541. PMID   17251932. S2CID   4373520.
  15. ↑ Campisi J (2005). "Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors". Cell. 120 (4): 513–22. doi: 10.1016/j.cell.2005.02.003 . PMID   15734683. S2CID   9559146.
  16. ↑ Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O (1995). "A Biomarker that Identifies Senescent Human Cells in Culture and in Aging Skin in vivo". Proceedings of the National Academy of Sciences. 92 (20): 9363–7. Bibcode:1995PNAS...92.9363D. doi: 10.1073/pnas.92.20.9363 . PMC   40985 . PMID   7568133.
  17. ↑ Narita M, Nũnez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW (2003). "Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence". Cell. 113 (6): 703–16. doi: 10.1016/S0092-8674(03)00401-X . PMID   12809602. S2CID   762586.
  18. ↑ Tuttle R, Simon M, Hitch DC, Maiorano JN, Hellan M, Ouellette J, Termuhlen P, Berberich SJ (18 June 2011). "Senescence-Associated Gene Ypel3 is Downregulated in Human Colon Tumors". Annals of Surgical Oncology. 18 (6): 1791–6. doi:10.1245/s10434-011-1558-x. PMID   21267786. S2CID   26038468.
  19. 1 2 Esteller M (2008). "Epigenetics in Cancer" (PDF). New England Journal of Medicine. 358 (11): 1148–59. doi:10.1056/NEJMra072067. hdl: 2445/176325 . PMID   18337604. S2CID   4636310.
  20. ↑ Costello JF, Frühwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomäki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O'Dorisio MS, Held WA, Cavenee WK, Plass C (2000). "Aberrant CpG-island methylation has non-random and tumour-type-specific patterns". Nature Genetics. 24 (2): 132–8. doi:10.1038/72785. PMID   10655057. S2CID   6273676.
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