YPEL3

Yippee-like 3 (Drosophila) is a is_associated_with::protein that in humans is encoded by the YPEL3 is_associated_with::gene. YPEL3 has growth inhibitory effects in normal and is_associated_with::tumor cell lines. One of five family members (YPEL1-5), YPEL3 was named in reference to its is_associated_with::Drosophila melanogaster is_associated_with::orthologue. Initially discovered in a gene expression profiling assay of is_associated_with::p53 activated is_associated_with::MCF7 cells, induction of YPEL3 has been shown to trigger permanent growth arrest or is_associated_with::cellular senescence in certain human normal and tumor cell types. is_associated_with::DNA methylation of a is_associated_with::CpG island near the YPEL3 promoter as well as histone acetylation may represent possible is_associated_with::epigenetic 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 drosophilia Yippee protein was identified as a putative is_associated_with::zinc finger motif containing protein exhibiting a high degree of conservation among the is_associated_with::cysteines and is_associated_with::histidines. 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 is_associated_with::apoptosis 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 Drosophilia Yippee protein was originally discovered in a yeast interaction trap screen when it was found to physically interact with Hyalophora cecropia is_associated_with::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. When analyzed at the is_associated_with::amino acid level, Drosophila melanogaster Yippee and YPEL1 displayed a high level of homology (76%). During later sequence analysis of human is_associated_with::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 is_associated_with::p53 dependent cell cycle arrest. While investigating the p53 is_associated_with::tumor suppressor protein, is_associated_with::microarray studies which targeted Hdmx and Hdm2, both p53 negative regulators, revealed YPEL3 as a potential p53 regulated gene in is_associated_with::MCF7 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 is_associated_with::cellular senescence pathway.

Regulation by p53
is_associated_with::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 is_associated_with::oncogenic and non-oncogenic. An important checkpoint in a complex pathway, activated p53 has been shown to bind is_associated_with::DNA and transcriptionally regulate genes that can mediate a variety of cellular growth processes including is_associated_with::DNA repair, growth arrest, is_associated_with::cellular senescence and is_associated_with::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 is_associated_with::MCF7 breast cancer cells following is_associated_with::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.

Cellular senescence
As a part of the p53 pathway response and its anti-proliferation role, cellular is_associated_with::senescence has gained attention for its working relationship with is_associated_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 is_associated_with::fibroblasts. Studies in U2OS osteosarcoma cells and is_associated_with::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.

Epigenetic modification
is_associated_with::Epigenetics is the study of changes in gene activity that do not involve alterations to genetic code, or is_associated_with::DNA. Instead, just above the is_associated_with::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 is_associated_with::cancer. Unlike genetic is_associated_with::mutations, epigenetic changes are considered reversible, although further study is needed.

Two common methods of epigenetic modification are is_associated_with::DNA methylation and histone modification. Specifically, hypermethylation of is_associated_with::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 is_associated_with::VHL (associated with von Hippel–Lindau disease), p16, hMLH1, and is_associated_with::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 is_associated_with::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 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.