Yippee-like 3 (Drosophila) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the YPEL3

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. YPEL3 has growth inhibitory effects in normal and

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

cell lines. One of five family members (YPEL1-5), YPEL3 was named in reference to its

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...

orthologue. Initially discovered in a gene expression profiling assay of

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

activated

MCF7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old White 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-wor ...

cells, induction of YPEL3 has been shown to trigger permanent growth arrest or

cellular senescence Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approxim ...

in certain human normal and tumor cell types.

DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts ...

of a

CpG island The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG i ...

near the YPEL3 promoter as well as histone acetylation may represent possible

epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...

mechanisms leading to decreased gene expression in human tumors.

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. The Drosophila Yippee protein was identified as a putative

zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...

motif containing protein exhibiting a high degree of conservation among the

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, some ...

s and

histidines Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the d ...

. 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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

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.

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 Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

organisms, ranging from fungi to humans. When analyzed at the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

level, Drosophila melanogaster Yippee and YPEL1 displayed a high level of homology (76%). During later sequence analysis of human

chromosome 22 Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and representing ...

, 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

dependent cell cycle arrest. While investigating the p53

tumor suppressor 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 re ...

protein,

microarray A microarray is a multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of genes from a sample (e.g. from a tissue). It is a two-dimensional array on a solid substrate—usually a glass slide or silicon ...

studies which targeted Hdmx and Hdm2, both p53 negative regulators, revealed YPEL3 as a potential p53 regulated gene in

breast cancer cells. 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

pathway.

Function

Regulation by 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 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 abnor ...

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 DNA repair is 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 radiation can cause DNA d ...

, growth arrest,

and

. 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

breast cancer cells following

RNAi RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by ...

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.

Cellular senescence

As a part of the p53 pathway response and its anti-proliferation role, cellular

senescence Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence invol ...

has gained attention for its working relationship with

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 A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

. Studies in U2OS osteosarcoma cells and

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.

Epigenetic modification

Epigenetics In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...

is the study of changes in gene activity that do not involve alterations to genetic code, or DNA. Instead, just above the

genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...

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 is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. Unlike genetic

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

, epigenetic changes are considered reversible, although further study is needed. Two common methods of epigenetic modification are

and histone modification. Specifically, hypermethylation of

CpG islands The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG i ...

( 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 (also known as p16INK4a, cyclin-dependent kinase inhibitor 2A, CDKN2A, multiple tumor suppressor 1 and numerous other synonyms), is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S p ...

, hMLH1, and

BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...

(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

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 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.

References

{{reflist, 35em Human proteins Senescence