YPEL3
Encyclopedia
Human YPEL3 is a recently discovered protein
encoded by the YPEL3 gene
, shown to have growth inhibitory effects in normal and tumor
cell lines. One of five family members (YPEL1-5), YPEL3 was named in reference to its Drosophila melanogaster
orthologue. Initially discovered in a gene expression profiling assay of p53
activated MCF7
cells, induction of YPEL3 has been shown to trigger permanent growth arrest or cellular senescence in certain human normal and tumor cell types. 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.
when studied in myeloid precursor cell lines . 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.
motif containing protein exhibiting a high degree of conservation among the cysteine
s and histidines. Zinc fingers function as structural platforms for DNA binding.
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.
organisms, ranging from fungi to humans. 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.
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. Investigation into its function lead to the discovery of YPEL3 being a novel protein whose growth suppressive activity is thought to be mediated through a cellular senescence pathway.
and transcriptionally regulate genes that can mediate a variety of cellular growth processes including DNA repair
, growth arrest, cellular senescence and apoptosis
. The importance of functioning p53 in the regulation of the cell cycle is evident in that 55% of human cancers exhibit p53 mutations.
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. 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.
has gained attention for its working relationship with tumor suppressor genes. 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). 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.
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. 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. As further possible evidence to its function, reduced expression of YPEL3 has been observed in ovarian, lung, and colon tumor cell lines.
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.
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. Hypermethylation seen in the promoters of tumor suppressor genes are cancer type specific, allowing each tumor type to be identifiable with an individual pattern. Such discoveries have lead 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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by the YPEL3 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, shown to have growth inhibitory effects in normal and tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cell lines. One of five family members (YPEL1-5), YPEL3 was named in reference to its Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
orthologue. Initially discovered in a gene expression profiling assay of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
activated MCF7
MCF7
MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old Caucasian woman. MCF-7 is the acronym of Michigan Cancer Foundation - 7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers...
cells, induction of YPEL3 has been shown to trigger permanent growth arrest or cellular senescence in certain human normal and tumor cell types. DNA methylation
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
of a CpG island
CpG island
In genetics, CpG islands or CG islands are genomic regions that contain a high frequency of CpG sites but to date objective definitions for CpG islands are limited. In mammalian genomes, CpG islands are typically 300-3,000 base pairs in length. They are in and near approximately 40% of promoters of...
near the YPEL3 promoter as well as histone acetylation may represent possible epigenetic mechanisms leading to decreased gene expression in human tumors.
Nomenclature
YPEL3 was first identified as murine SUAP, named for small unstable apoptotic protein because of its apparent role in cellular growth inhibition via apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
when studied in myeloid precursor cell lines . SUAP later attained its current designation as YPEL3 (Yippee like three), after it was discovered to be one of five human genes possessing homology
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
with the Drosophila Yippee protein.
Location and Structure
The drosophilia Yippee protein was identified as a putative zinc fingerZinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...
motif containing protein exhibiting a high degree of conservation among the cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
s and histidines. Zinc fingers function as structural platforms for DNA binding.
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.
Discovery
The Drosophilia 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 eukaryoticEukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
organisms, ranging from fungi to humans. When analyzed at the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
level, Drosophila melanogaster Yippee and YPEL1 displayed a high level of homology (76%). During later sequence analysis of human chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
22, researchers identified a gene family YPEL1-YPEL5, which had high homology with the Drosophila Yippee gene.
YPEL3’s role as a novel tumor suppressor and its involvement in cellular proliferation were discovered during experiments to investigate p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
dependent cell cycle arrest. While investigating the p53 tumor suppressor protein, microarray
Microarray
A microarray is a multiplex lab-on-a-chip. It is a 2D array on a solid substrate that assays large amounts of biological material using high-throughput screening methods.Types of microarrays include:...
studies which targeted Hdmx and Hdm2
Mdm2
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
, both p53 negative regulators, revealed YPEL3 as a potential p53 regulated gene in MCF7
MCF7
MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old Caucasian woman. MCF-7 is the acronym of Michigan Cancer Foundation - 7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers...
breast cancer cells. Investigation into its function lead to the discovery of YPEL3 being a novel protein whose growth suppressive activity is thought to be mediated through a cellular senescence pathway.
YPEL3 and 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 DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and transcriptionally regulate genes that can mediate a variety of cellular growth processes including DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
, growth arrest, cellular senescence and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. The importance of functioning p53 in the regulation of the cell cycle is evident in that 55% of human cancers exhibit p53 mutations.
YPEL3 was discovered to be a possible p53 target after a screen for such genes was performed in MCF7
MCF7
MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old Caucasian woman. MCF-7 is the acronym of Michigan Cancer Foundation - 7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers...
breast cancer cells following RNAi
RNAI
RNAI is a non-coding RNA that is an antisense repressor of the replication of some E. coli plasmids, including ColE1. Plasmid replication is usually initiated by RNAII, which acts as a primer by binding to its template DNA. The complementary RNAI binds RNAII prohibiting it from its initiation role...
knockdown of p53 negative inhibitors. 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.
YPEL3 and Cellular Senescence
As a part of the p53 pathway response and its anti-proliferation role, cellular senescenceSenescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
has gained attention for its working relationship with tumor suppressor genes. 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). 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.
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. YPEL3 has been shown to trigger premature senescence when studied in IMR90 primary human fibroblasts. Studies in U2OS osteosarcoma cells and MCF7
MCF7
MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old Caucasian woman. MCF-7 is the acronym of Michigan Cancer Foundation - 7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers...
breast cancer cells have also demonstrated increased cellular senescence upon YPEL3 induction. As further possible evidence to its function, reduced expression of YPEL3 has been observed in ovarian, lung, and colon tumor cell lines.
YPEL3 and Epigenetic Modification
EpigeneticsEpigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
is the study of changes in gene activity that do not involve alterations to genetic code, or DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. Instead, just above the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
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
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Unlike genetic mutations, epigenetic changes are considered reversible, although further study is needed.
Two common methods of epigenetic modification are DNA methylation
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
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
P16
P16, P-16, or P.6 may refer to:* p16 , also known as p16Ink4A, a gene involved in tumor suppression* AMC Schneider P 16, a French halftrack developed in the 1920s...
, hMLH1, and BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
(a gene associated with breast cancer susceptibility), hypermethylation of the CpG-island has been shown to be a method of gene inactivation.
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
CpG island
In genetics, CpG islands or CG islands are genomic regions that contain a high frequency of CpG sites but to date objective definitions for CpG islands are limited. In mammalian genomes, CpG islands are typically 300-3,000 base pairs in length. They are in and near approximately 40% of promoters of...
immediately upstream of the YPEL3 promoter has been seen to down regulate YPEL3 expression. Hypermethylation seen in the promoters of tumor suppressor genes are cancer type specific, allowing each tumor type to be identifiable with an individual pattern. Such discoveries have lead 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.