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PIWIL2 (piwi-like RNA-mediated gene silencing 2)

Written2014-03Jian-Xin Gao, Ning Liu, Hai-Long Wu
State Key Laboratory of Oncogene, Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (JXG); Laboratory of Tumorigenesis, Immunity, Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (JXG, NL, HLW)

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Identity

Alias_namespiwi-like 2 (Drosophila)
Alias_symbol (synonym)HILI
FLJ10351
Mili
CT80
Other aliasPIWIL1L
mili
HGNC (Hugo) PIWIL2
LocusID (NCBI) 55124
Atlas_Id 41724
Location 8p21.3  [Link to chromosome band 8p21]
Location_base_pair Starts at 22275567 and ends at 22356071 bp from pter ( according to hg19-Feb_2009)  [Mapping PIWIL2.png]
Local_order POLR3D-LOC100507071-PIWIL2-SLC39A14-PPP3CC
Fusion genes
(updated 2016)
PIWIL2 (8p21.3) / ROCK2 (2p25.1)PIWIL2 (8p21.3) / VPS54 (2p14)PPP3CC (8p21.3) / PIWIL2 (8p21.3)
Note Human PIWIL2 or HiLi gene belongs to an evolutionarily conserved PIWI clades of Argonaute gene family that comprises four members of Argonaute genes (AGO1, AGO2, AGO3 and AGO4) and four members of PIWI genes (PIWIL1/HIWI, PIWIL2/HILI, PIWIL3 and PIWIL4/HIWI2) (Sasaki et al., 2003). While the PIWI family genes are exclusively expressed in the testis, the AGO family genes are ubiquitously expressed in adult tissues (Sasaki et al., 2003). All Argonaute family genes contain a central PAZ motif and a C-terminal PIWI motif (Sasaki et al., 2003).They form a RNA-induced silencing complex (RISC) to regulate a variety of biological functions through binding small RNAs (Hutvagner and Simard, 2008). PIWI genes are required for the functions in development and maintenance of germline stem cells (Cox et al., 2000).

DNA/RNA

Note The ortholog of Drosophila PIWI gene was identified as PIWIL1/HIWI in a human testis cDNA libray (Qiao et al., 2002), which is required for self-renewing and asymmetry division of germline stem cells (Lin and Spradling, 1997). PIWIL2/HILI was cloned by polymerase chain reaction (PCR) of a testis cDNA library while searching databases for homologs of PIWIL1/HIWI (Sasaki et al., 2003). Normally the transcripts (mRNAs) of PIWIL2 were exclusively found expressed in testis (Sasaki et al., 2003), but it was widely dentified in various types of tumor cell lines (Lee et al., 2006; Ye et al., 2010) and stressed somatic cells with DNA damages (Yin et al., 2011b). PIWIL2/MILI was also cloned in mouse and its transcripts were only detected in the testis and spermatogonia (Wang et al., 2001).
 
  Figure 1. Diagram of Location of PIWIL2/HILI gene and its transcript variants. PIWIL2 is located in chromosome 8 at locus 8p21.3. Six transcript variants are shown.
Description HILI is located in chromosome 8p21.3, starting from 22132810 and ending at 22215076 bp (ENSG00000197181), encompasses 82266 bp of DNA and consists of 23 exons (Figure 1).
Transcription There are at least six transcript variants of human PIWIL2 (Figure 2). The exon 1 of variants 1 and 3 is different in size and non-coding, but they have identical open reading frame (ORF), generating identical peptides. The variant 2 has the exon 1 with the same size as variant 1 but is lack of exon 22. The variant 4 is considered to be a retained intron. The variant 5 coding Piwil2-like (PL2L) proteins 60 (PL2L60) was found in the testis or tumors, which is a product of PIWIL2 alternatively activated by a putative intragenic promoter (Ye et al., 2010). The variant 6 is predicted by computer analysis and probably associated with multiple polyadenylation sites.
The variant 1 (PIWIL2-001; ENST00000356766) is a canonical one, mapping to chromosome 8: 22132810-22215076 with 82.27 kb, containing 23 exons with transcript length of 5128 bps. Twenty two exons are coding one with translation length of 973 residues.
The variant 2 (PIWIL2-002; ENST00000521356) has 22 exons containing 21 coding exons, mapping to chromosome 8: 22132850-22213584 with 80.73 kb. The transcript length is 3488 bps with translation length of 937 residues.
The variant 3 (PIWIL2-003; ENST00000454009) has 23 exons with transcript length of 3442 bps, mapping to chromosome 8: 22133080-22213029 with 79.95 kb. Twenty two coding exons are translated into 973 residues, same as the variant 1.
The variant 4 (PIWIL2-004; ENST00000519884) has 3 non-coding exons (intron retention), mapping to chromosome 8: 22210312-22213601 with 3.29 kb. Transcript length is 1262 bps.
The variant 5 [PIWIL2-like proteins 60 (PL2L60); AK027497] has 13 exons with transcript length of 2272 bps, mapping to chromosome 8: 22161569-22213584 with 52.015 kb. The transcript is transcribed by a predicted promoter up-stream of the exon 11, and the translation length is 530 residues (Ota et al., 2004; Ye et al., 2010).
The variant 6 [PREDICTED: Homo sapiens piwi-like RNA-mediated gene silencing 2 (PIWIL2), transcript variant X2, mRNA] has 20 exons with transcript length of 2677 bps, mapping to chromosome 8: 22132829-22179503 with 46.674 kb. The translation length is 804 residues (NCBI Reference Sequence: XM_005273551.1).
In addition to the defined transcripts listed above, there are several potentially alternatively transcribed transcripts resulted from intragenic activation of promoters of PIWIL2, such as PL2L50 and PL2L42 (Ye et al., 2010).
Pseudogene No pseudogene has been found so far.

Protein

Note HILI proteins are the products of HILI gene, belonging to the PIWI subfamily of Argonaute family proteins. The Argonaute family proteins contain two evolutionarily conserved motifs: PAZ and PIWI domains (Carmell et al., 2002). The PAZ domain is named after the proteins Piwi Argonaut and Zwille, composing of two subdomains. One subdomain is similar to the OB fold, which is well known as a single-stranded nucleic acid binding fold. The second subdomain is composed of a beta-hairpin followed by an alpha-helix. The 3' ends of single-stranded regions of RNA binds in low-affinity in the cleft between the two subdomains. Although PAZ may not be a primary nucleic acid binding site in Dicer or RISC, it may contribute to the specific and productive incorporation of siRNAs and miRNAs into the RNAi pathway. The PIWI domain is named after the Drosophila protein PIWI (P-element induced wimpy testis), which is essential for gametogenesis and maintenance of asymmetry division of germline stem cells (Cox et al., 1998; Cox et al., 2000; Deng and Lin, 2001; Lin and Spradling, 1997). The function of this domain is the dsRNA guided hydrolysis of ssRNA. Crystal structural analysis of Argonaute reveals that PIWI is an RNase H domain, and identifies Argonaute as Slicer, the enzyme that cleaves mRNA in the RNAi RISC complex (Song et al., 2004). The PIWI domain core has a tertiary structure belonging to the RNase H family of enzymes. By analogy to RNase H enzymes which cleave single-stranded RNA guided by the DNA strand in an RNA/DNA hybrid, the PIWI domain can be inferred to cleave single-stranded RNA, for example mRNA, guided by double stranded siRNA (Letunic et al., 2012; Schultz et al., 1998).
The Argonaute family proteins can be categorized into AGO and PIWI subfamily (Carmell et al., 2002). Both AGO and PIWI proteins can form transcriptional complexes with small RNAs to regulate gene expression. Normally AGO subfamily proteins are ubiquitously expressed in adult tissues to regulate various cell functions through binding exogenous 20-25 nucleotide (nt) small interfering RNAs (siRNAs) or endogenous 22-nt microRNAs (Carmell et al., 2002); whereas PIWI proteins are exclusively expressed in embryonic developmental stages and/or testis to regulate germline development through binding 24-31 nt piwi-interacting RNAs (piRNAs) (Lim et al., 2013b). Like all other Argonaute family members, HILI contains a central PAZ motif and a C-terminal PIWI motif (Figure 2). Aberrant or ectopic expression of HILI proteins in adult issues is likely associated with tumorigenesis (Peng and Lin, 2013; Suzuki et al., 2012).
 
  Figure 2. Diagram of PIWIL2/HILI protein. The protein structure of PIWIL2 consists of PAZ and PIWI domains. A third functional domain of PIWI proteins, MID domain (not shown) that lies between PAZ and PIWI domains, binds to the 5' phosphates of small RNAs and thus anchors small RNAs onto the PIWI protein, has not been clearly defined in PIWIL2.
Description Six HILI isoforms of transcripts have been described (Figure 1). The HILI protein contains two characteristic domains: a PAZ domain (aa 390-524) and a PIWI domain (aa 668-956). Transcripts PIWIL2-001 (5128 bp), PIWIL2-002 (3488 bp), PIWIL2-003 (3442 bp) and PL2L-60 (2288 bp) encodes three variants of PIWIL2 proteins. Transcripts PIWIL2-001 and PIWIL2-003 have identical open reading frame (ORF) and encode an identical peptide of 973 amino acids (109.8 kDa). Transcript PIWIL2-002 encodes a variant of 937 residues (105.8 kDa) with a complete PAZ domain (aa 390-524) and a spliced PIWI domain (aa 668-887). PL2L-60 mRNA encodes a variant of 530 residues (59.85 kDa) with a truncated PAZ domain (aa 1-61) and a complete PIWI domain (aa 69-514). PIWIL2-004 does not encode protein product.
There are at least four putative PL2L proteins including PL2L60, PL2L50, PL2L40 and PL2L40, which are the products of intragenic promoter activation of PIWIL2 and truncated at various N terminal sites of PIWIL2. Human PL2L60 has been identified and characterized (Ye et al., 2010).
Argonaute proteins contain amino-terminal (N), PAZ (PIWI-ARGONAUTE-ZWILLE), MID (middle) and PIWI (P-element induced wimpy testis) domains. N domain assists the loading of small RNA and unwinding of the RNA duplex (Kwak and Tomari, 2012). PAZ domain and M domain anchors 3'-end and 5'-end of the small RNA, respectively, by providing a specific binding pocket (Jinek and Doudna, 2009). PAZ domain can bind small regulatory RNAs such as miRNAs to AGO subfamily proteins and piRNAs to PIWI subfamily proteins, whereas PIWI domain bound by mRNA contains RNase H fold, probably functioning as endonuclease to cleave the bound mRNA that is complementary to the bound small RNA (Carmell et al., 2002; Jinek and Doudna, 2009; Parker and Barford, 2006; Song et al., 2003).
Expression Normally, HILI is exclusively expressed in the spermatogonia and spermatocytes of the testis (Sasaki et al., 2003) and in the female oocytes and supporting cells of human (Lim et al., 2013b). However, it can be temporarily activated in somatic cells in responding to DNA damages and in the primary cancers, and its intragenically activated products such as PL2L60 are expressed in various types of tumor cell lines (Ye et al., 2010; Yin et al., 2011b).
Localisation HILI and its variants can be found in cytoplasm, nucleus or both of germline stem cells and tumor cells (Lee et al., 2010; Liu et al., 2010; Ye et al., 2010). They may present in chromatoid body, a probable component of the meiotic nuage, also named P granule, a germ-cell-specific organelle required to repress transposon during meiosis (Lim et al., 2013a; Wang et al., 2009). The significance of HILI expression in cytoplasm versus in nucleus remains to be elucidated.
Function PIWIL2 has multiple functions in germline development and tumorigenesis. The functions of PIWIL2 are mainly mediated by two motifs: PAZ and PIWI domains, which are highly conserved evolutionarily. PIWIL2 is associated with ribonuclease type III (DICER 1), an important component of RISC complexes (Sasaki et al., 2003).
PIWIL2 plays critical roles in the PIWI/PIWI-interacting RNA (piRNA) pathway, which is essential for spermatogenesis and transposon repression. The associated factors of the PIWI-piRNA pathway may include VASA, MAELSTROM, and TUDOR domain proteins. In coordination with the associated factors, PIWIL2 mediates piRNA biosynthesis, transcriptional silencing (Li et al., 2012), translational regulation (Unhavaithaya et al., 2009), and DNA methylation of transposons (Kuramochi-Miyagawa et al., 2008). In a mouse model, piRNA was required for de novo methylation of the differentially methylated region (DMR) of the imprinted mouse Rasgrf1 locus, but not other paternally imprinted loci, suggesting that piRNAs and a target RNA direct the sequence-specific methylation of Rasgrf1 (Watanabe et al., 2011). PIWIL2 also participate posttranslational modification through interaction with Tudor domain-containing protein TDRD1. Arginine methylation of Piwil2 proteins by PRMT5 is required for its interaction with Tdrd1 and subsequent localization to the meiotic nuage, also named P granule (Vagin et al., 2009).
In germline development, PIWIL2 may regulate the self-renewal of germline stem cells (Unhavaithaya et al., 2009) and maintain genomic integrity through interacting with piRNA to suppress the mobility of transposons, such as long interspersed nuclear elements-1 (L1, also known as LINE-1) (Marchetto et al., 2013). The piRNAs are 26 to 31 nucleotides in length and thus clearly distinct from the 21 to 23 nucleotides of microRNAs (miRNAs) or short interfering RNAs (siRNAs). PIWIL2 mediates spermatogenesis in mouse and human. DNA methylation of retrotransponsons was controlled and regulated by Piwil2 partnered with piRNA (Aravin et al., 2006; Aravin et al., 2007; Kuramochi-Miyagawa et al., 2008; Xu et al., 2008). In human, male infertility is associated with inactivation of PIWI pathway caused by the promoter hypermethylation of PIWIL2 and TDRD1. The epigenetic inactivation of PIWI gene pathway resulted in a defective production of piRNAs and a hypomethylation of the LINE-1 repetitive sequence in the affected patients (Heyn et al., 2012). In mouse testis piRNAs accumulated at the onset of meiosis (Aravin et al., 2006), silencing L1 in meiotic pachytene cells (Di Giacomo et al., 2013). PIWIL2/MILI deficient mice were infertile (Kuramochi-Miyagawa et al., 2004). Mili-mediated secondary piRNA biogenesis fuels piRNA amplification that is absolutely required for LINE-1 silencing (De Fazio et al., 2011).
In tumor development, PIWIL2 may play multiple functions, probably depending on its activating status (Ye et al., 2010). At the beginning of tumorigenesis, PIWIL2 could temporally respond to environmental stresses, such as ionizing radiation, ultraviolet radiation and genotoxic agents, mediating chromatin relaxation to promote DNA repair and thus playing a protective role (Yin et al., 2011b). PIWIL2 expression was enhanced in testicular seminomas, but not in testicular nonseminomatous tumors (Lee et al., 2006). PIWIL2 was also expressed in human and mouse tumors of various tissues (Lee et al., 2006; Ye et al., 2010). Lee et al. showed that overexpression of PIWIL2 in a murine fibroblast cell line or human breast cancer stem cells resulted in inhibiting apoptosis and promoting proliferation and cell transformation via a signal transducer and activator of transcription 3 (STAT3)/BCLXL signaling pathway (Lee et al., 2010; Lee et al., 2006). Chen et al. demonstrated that Piwil2 transcripts was constitutively and stably expressed in murine precancerous stem cells (pCSCs) and overexpression of Piwil2 resulted in hematopoietic stem cell proliferation and transformation (Chen et al., 2007). Overexpression or ectopic expression of PIWIL2 in normal cells appeared to be associated with cell transformation and tumor initiation (Shahali et al., 2013). However, whole length of PIWIL2 was only detected in apoptotic cancer cells of primary cancers (Ye et al., 2010). PIWIL2 variants might determine the fate of a cancer cells. Ye et al. demonstrated that PIWIL2 gene could be activated via intragenic promoters, leading to expression of PIWIL2-like (PL2L) proteins, such as PL2L60, which may promote tumor survival and growth through regulating NF-κB translocation to nucleus (Ye et al., 2010). The alienation activation of PIWIL2 appeared to be associated with tumor malignancy, because PL2L proteins were mainly detected in proliferating cancer cells and cancer cell lines as well as metastatic cancer cells (Ye et al., 2010). Elucidation of the roles of PIWIL2 variants in tumorigenesis is critical for understanding complex functions of PIWIL2.
The PIWIL2 appears to be involved in various signaling transduction pathways. In TGF-β mediated signaling pathway, it suppressed TGF-β signaling pathway by physically associating with Hsp90, preventing formation of Hsp90-TβR heteromeric complexes and improving ubiquitination and degradation of TβRs in a manner depending on the ubiquitin E3 ligase Smurf2 (Zhang et al., 2012). In p53 signaling pathway, the PIWIL2 repressed the tumor suppressor P53 in human cancer cells. Its PAZ domain directly associated with STAT3 protein to form a PIWIL2/STAT3/c-Src triple proteins complex, which resulted in STAT3 phosphorylation by c-Src and translocation to nucleus, then binding to P53 promoter and repressing its transcription (Lu et al., 2012). In colon cancer cell lines, the PIWIL2 could modulate matrix metallopeptidase 9 (MMP9) transcriptional activities (Li et al., 2012). In addition, silencing PIWIL2 suppressed the expression of STAT3, down-regulating Bcl-X(L) and cyclin D1, leading to a reduction of cell proliferation and survival (Lee et al., 2010).
PIWIL2 may also play important roles in maintaining genomic integrity by suppressing retrotransposons, stabilizing heterochromatin structure, and regulating target genes during meiosis and mitosis. In the murine mesenchymal stem cells (MSC), Piwil2 is expressed in the cytoplasm of metaphase. In contrasting to promoting cell proliferation (Lee et al., 2010a; Lee et al., 2006; Lu et al., 2012; Zhang et al., 2012), Piwil2 did not do so in the MSCs, because knockdown of PiwiL2 with a specific siRNA enhanced cell proliferation, significantly increased the number of cells in G1/S and G2/M cell cycle phases and was associated with increased expression of cell cycle genes CCND1, CDK8, microtubule regulation genes, and decreased expression of tumor suppressors Cables 1, LATS, and Cxxc4 (Wu et al., 2010).
Along with piRNAs PIWIL2 could suppress LINE1 in tumor cells. A set of piRNAs and other repeat-associated small RNAs were observed in HeLa cells. By using in situ hybridization, piR-49322 was localized in the nucleolus and around the periphery of nuclear membrane in HeLa cells. Following the overexpression of HILI, the retrotransposon element LINE1 was significantly repressed, while LINE1-associated small RNAs decreased in abundance (Wu et al., 2013).
PIWIL2 might contribute to great ape evolution. Comparative gene expression analysis of human and nonhuman primate iPS cells revealed that levels of L1-restricting factors or DNA cytosine deaminase APOBEC3B (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3B) and PIWIL2 inversely correlated with L1 mobility and endogenous L1 mRNA levels. The increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans suggests that differences in L1 mobility may have differentially shaped the genomes of humans and nonhuman primates (Burns et al., 2013; Marchetto et al., 2013).
In addition, PIWIL2 was upregulated in the TGF-β induced EMT-type breast cancer stem cells (CD44+CD24-),forming a complex with piR-923 and promoting Latexin (LXN) promoter methylation (Zhang et al., 2013).
Homology The PIWIL2 gene is conserved in zebrafish, mouse, rat, dog, cow and chimpanzee.

Mutations

Note Numerous mutations of PIWIL2/HILI have been detected in various types of primary cancers, including the cancers of breast, lung, liver, kidney, ovary, pancreas and large intestine. Copy number variation (CNV) has also been observed in the cancers of breast, large intestine, kidney, lung, ovary, pancreas, endometrium, central nervous system, hematopoietic and lymphoid, and skin (CONAN).

Implicated in

Note
  
Entity Various cancers
Note Although PIWIL2 is exclusively expressed in the testis of human and animals, it has been detected in the stressing cells (Yin et al., 2011b) and almost all the various types of cancer cell lines tested of human and animals (Chen et al., 2007a; Lee et al., 2006; Ye et al., 2010) as well as in various primary cancers, including leukemia, breast tumor, medulloblastoma, rhabdomyosarcoma, colon cancer, cervical cancer and papillary thyroid carcinoma (He et al., 2010; Lee et al., 2006; Li et al., 2010; Yin et al., 2011a). Interestingly, PIWIL2 transcripts or proteins were enriched in precancerous stem cells, and cancer stem cells isolated from breast cancer and cervical cancer (Chen et al., 2007; Feng et al., 2009; Lee et al., 2010). The intragenic promoter activation resulted in alienation products of PIWIL2, such as PL2L60 protein, promoting tumor cell growth and metastasis, while full length of PIWIL2 was mainly detected in the apoptosing cancer cells of primary cancers (Ye et al., 2010). It should be noted that the failure to detect PIWIL2 transcripts in some cancers such as bladder cancers is likely associated with false negativity from RT-PCR analysis in which the primers used did not complement the alternatively transcribed mRNA (Ye et al., 2010).
  
  
Entity Seminoma
Note Testicular germ cell tumors can be categorized as seminoma and non-seminoma. PIWIL2 was detected in human seminoma but not in non-seminomatous tumors (Lee et al., 2006). However, a recent report showed that in addition to testicular germ cell tumor cell lines, PIWIL1, PIWIL2, PIWIL4, and TDRD1 in primary seminoma and non-seminoma testicular tumors were silenced by promoter CpG island hypermethylation. Importantly, these epigenetic lesions were associated with piRNA downregulation and loss of DNA methylation of the LINE-1 repetitive sequences (Ferreira et al., 2014).
  
  
Entity Bladder cancer
Note The PIWIL2 transcripts were reportedly not detected by qRT-PCR in bladder cancer cell lines and primary bladder cancers (Nikpour et al., 2009). However, a recent report showed that the PIWIL2 mRNA was detectable by qRT-PCR in 76.08% (35/46) patients with the bladder urothelial carcinoma (Cao et al., 2012). The conflicting results may be caused by the primers used, a pair of which did not complement the truncated transcripts of PIWIL2 in tumors (Ye et al., 2010).
  
  
Entity Cervical cancer
Note The PIWIL2 can be detected by immunohistochemical staining (IHS) in various stages of human cervical squamous cell carcinomas and adenocarcinomas. It was also detected in some metaplastic epithelial cells as well as histologically "normal" appearing tissues adjacent to malignant lesions. In Papanicolaou (Pap) test, PIWIL2 was also detected by immunocytological staining (ICS) in atypical glandular cells (AGC), low-grade (LSIL) and high-grade squamous intraepithelial lesions (HSIL). PIWIL2 is a more sensitive biomarker than p16, which was not always concomitantly detected in the same specimens (He et al., 2010). Especially, a subpopulation of cancer cells with stem-like properties expressed higher level of PIWIL2 (Feng et al., 2009).
  
  
Entity Colon cancer
Note The PIWIL2 and PIWIL4 were detected by immunohistochemistry (IHC) in colon cancers. The former was detected at the occurrence of colon cancers, while the later was associated with distant metastasis of the cancers (Li et al., 2010). In another report, the PIWIL2 was detected by IHC in primary colon cancer tissue and lymph node metastasis (LNM) lesions and significantly correlated with clinicopathological invasiveness, poorer five-year metastasis-free survival and poorer overall survival (Li et al., 2012; Oh et al., 2012). In addition, PIWIL2 expression was associated with poor differentiation, aggressive invasion, and perineural invasion in colorectal carcinomas (Oh et al., 2012).
  
  
Entity Breast cancer
Note The PIWIL2 was detected, though variable in levels, by IHS in almost all of the breast cancer samples at premalignant and malignant stages. It was detected in cytoplasm (Cyt), nucleus (N) or both cytoplasm and nucleus (C-N). The N pattern was less observed in precancerous lesions, whereas all the three patterns were observed in invasive and metastatic cancers. While the Cyt pattern correlated with ER expression; N pattern correlated with Ki67 expression. The shift of Cyt --> C-N --> N patterns were associated with the reduction of ER expression and an increase of Ki67 expressions (Liu et al., 2010). In primary breast cancers, full length of PIWIL2 was mainly expressed in apoptotosing cells while PL2L proteins, the products of PIWIL2 that was alternatively activated by intragenic promoters, appeared to be expressed in proliferating cancer cells and metastatic cancer cells (Ye et al., 2010).
Like observed in cervical cancers, PIWIL2 was predominantly expressed in the breast cancer stem cells (Lee et al., 2010a; Zhang et al., 2013). Up to 90% of invasive carcinomas and 81% of carcinomas in situ expressed highest level of PIWIL2 (Lee et al., 2010).
  
  
Entity Thyroid cancer
Note Piwil2 proteins and mRNAs were detected by IHS and in situ hybridization (ISH) in 88.3% and 88.5% papillary thyroid carcinoma (PTC), respectively. The level of PIWIL2 expression was associated with the invasiveness and metastasis of PTC (Yin et al., 2011a).
  
  
Entity Gastric cancer
Note The expression of PIWIL2 detected by IHS was significantly higher in the gastric tumor tissue than that in adjacent non-tumor tissue. Expression level of PIWIL2 was positively correlated with the T stage, lymph node metastasis and clinical TNM (cTNM). Moreover, elevated PIWIL2 expression in cancer tissue predicted poorer overall survival (OS) compared with the group of lower expression (Wang et al., 2012).
  
  
Entity Sarcoma
Note PIWIL2 expression in 125 soft tissue sarcoma (STS) samples together with PIWIL3 and PIWIL4 expressions were measured by real-time PCR (qPCR). Low PIWIL2 or PIWIL4 mRNA expressions were significantly associated with a poor prognosis. Low expression of both genes was associated with a 2.58-fold increased risk of tumor-related death. PIWIL4 and the combined PIWIL2 and PIWIL4 mRNA levels correlated significantly with prognosis only for female but not for male patients. However, the combined low PIWIL 2 and PIWIL3 transcript levels were associated with worse survival for male patients (Greither et al., 2012).
  
  
Entity Prostate cancer
Note The PIWIL2 was detected using Whole Human Genome Oligo Microarrays in prostate cancer. Compared to peripheral zone, PIWIL2 was down-regulated in poorly differentiated tumors but not in moderately differentiated tumors (Shaikhibrahim et al., 2013).
  
  
Entity Leukemia
Note PIWIL2 expression in acute myeloid leukemia (AML) was analyzed by real-time PCR and differed in expression pattern in a gender-dependent manner (Shaikhibrahim et al., 2013).
  
  
Entity Ovarian cancer
Note The PIWIL2 was detected by IHS in the primary ovarian cancer and metastatic tissues from the patients with stage III epithelial ovarian cancer (EOC). Other PIWI proteins such as PIWIL1, PlWlL3, and PIWIL4 were also detected in the primary tumor and metastatic tissues (Chen et al., 2013).
  
  
Entity Male infertility
Note Defective PIWIL2 expression is associated with male infertility in mouse and human (Heyn et al., 2012; Kuramochi-Miyagawa et al., 2004). In human, the disorder was likely associated with the promoter hypermethylation of PIWIL2 and its associated factor TDRD1, which resulted in a defective production of piRNAs and a hypomethylation of the LINE-1 repetitive sequence in the affected patients (Heyn et al., 2012). The presence of PIWIL2 in oocytes or ovary also suggests that it may participate in similar functions during oogenesis in females (Lim et al., 2013b; Olesen et al., 2007). The link of PIWIL2/HILI single nucleotide polymorphisms (SNPs) with spermatogenic failure has not been established (Gu et al., 2010).
  

To be noted

Acknowledgement: The manuscript was supported by National Natural Science Foundation of China (JXG, Grants no.81171940 and 81372188).

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Identification and characterization of cancer stem-like cells from primary carcinoma of the cervix uteri.
Feng D, Peng C, Li C, Zhou Y, Li M, Ling B, Wei H, Tian Z.
Oncol Rep. 2009 Nov;22(5):1129-34.
PMID 19787230
 
Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis.
Ferreira HJ, Heyn H, Garcia del Muro X, Vidal A, Larriba S, Munoz C, Villanueva A, Esteller M.
Epigenetics. 2014 Jan 1;9(1):113-8. doi: 10.4161/epi.27237. Epub 2013 Nov 18.
PMID 24247010
 
Expression of human Piwi-like genes is associated with prognosis for soft tissue sarcoma patients.
Greither T, Koser F, Kappler M, Bache M, Lautenschlager C, Gobel S, Holzhausen HJ, Wach S, Wurl P, Taubert H.
BMC Cancer. 2012 Jun 29;12:272. doi: 10.1186/1471-2407-12-272.
PMID 22748119
 
Genetic variants in Piwi-interacting RNA pathway genes confer susceptibility to spermatogenic failure in a Chinese population.
Gu A, Ji G, Shi X, Long Y, Xia Y, Song L, Wang S, Wang X.
Hum Reprod. 2010 Dec;25(12):2955-61. doi: 10.1093/humrep/deq274. Epub 2010 Oct 11.
PMID 20940137
 
Piwil2 expressed in various stages of cervical neoplasia is a potential complementary marker for p16.
He G, Chen L, Ye Y, Xiao Y, Hua K, Jarjoura D, Nakano T, Barsky SH, Shen R, Gao JX.
Am J Transl Res. 2010 Mar 25;2(2):156-69.
PMID 20407605
 
Epigenetic disruption of the PIWI pathway in human spermatogenic disorders.
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PLoS One. 2012;7(10):e47892. doi: 10.1371/journal.pone.0047892. Epub 2012 Oct 24.
PMID 23112866
 
Argonaute proteins: key players in RNA silencing.
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Nat Rev Mol Cell Biol. 2008 Jan;9(1):22-32. (REVIEW)
PMID 18073770
 
A three-dimensional view of the molecular machinery of RNA interference.
Jinek M, Doudna JA.
Nature. 2009 Jan 22;457(7228):405-12. doi: 10.1038/nature07755. (REVIEW)
PMID 19158786
 
DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes.
Kuramochi-Miyagawa S, Watanabe T, Gotoh K, Totoki Y, Toyoda A, Ikawa M, Asada N, Kojima K, Yamaguchi Y, Ijiri TW, Hata K, Li E, Matsuda Y, Kimura T, Okabe M, Sakaki Y, Sasaki H, Nakano T.
Genes Dev. 2008 Apr 1;22(7):908-17. doi: 10.1101/gad.1640708.
PMID 18381894
 
The N domain of Argonaute drives duplex unwinding during RISC assembly.
Kwak PB, Tomari Y.
Nat Struct Mol Biol. 2012 Jan 10;19(2):145-51. doi: 10.1038/nsmb.2232.
PMID 22233755
 
Pathways of proliferation and antiapoptosis driven in breast cancer stem cells by stem cell protein piwil2.
Lee JH, Jung C, Javadian-Elyaderani P, Schweyer S, Schutte D, Shoukier M, Karimi-Busheri F, Weinfeld M, Rasouli-Nia A, Hengstler JG, Mantilla A, Soleimanpour-Lichaei HR, Engel W, Robson CN, Nayernia K.
Cancer Res. 2010 Jun 1;70(11):4569-79. doi: 10.1158/0008-5472.CAN-09-2670. Epub 2010 May 11.
PMID 20460541
 
Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway.
Lee JH, Schutte D, Wulf G, Fuzesi L, Radzun HJ, Schweyer S, Engel W, Nayernia K.
Hum Mol Genet. 2006 Jan 15;15(2):201-11. Epub 2005 Dec 23.
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Nucleic Acids Res. 2012 Jan;40(Database issue):D302-5. doi: 10.1093/nar/gkr931. Epub 2011 Nov 3.
PMID 22053084
 
Piwil2 modulates the proliferation and metastasis of colon cancer via regulation of matrix metallopeptidase 9 transcriptional activity.
Li D, Sun X, Yan D, Huang J, Luo Q, Tang H, Peng Z.
Exp Biol Med (Maywood). 2012 Oct;237(10):1231-40. doi: 10.1258/ebm.2012.011380. Epub 2012 Oct 26.
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BMC Cancer. 2010 Feb 10;10:38. doi: 10.1186/1471-2407-10-38.
PMID 20146808
 
The nuage mediates retrotransposon silencing in mouse primordial ovarian follicles.
Lim AK, Lorthongpanich C, Chew TG, Tan CW, Shue YT, Balu S, Gounko N, Kuramochi-Miyagawa S, Matzuk MM, Chuma S, Messerschmidt DM, Solter D, Knowles BB.
Development. 2013a Sep;140(18):3819-25. doi: 10.1242/dev.099184. Epub 2013 Aug 7.
PMID 23924633
 
Conservation and expression of PIWI-interacting RNA pathway genes in male and female adult gonad of amniotes.
Lim SL, Tsend-Ayush E, Kortschak RD, Jacob R, Ricciardelli C, Oehler MK, Grutzner F.
Biol Reprod. 2013b Dec 12;89(6):136. doi: 10.1095/biolreprod.113.111211. Print 2013 Dec.
PMID 24108303
 
A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary.
Lin H, Spradling AC.
Development. 1997 Jun;124(12):2463-76.
PMID 9199372
 
Piwil2 is expressed in various stages of breast cancers and has the potential to be used as a novel biomarker.
Liu JJ, Shen R, Chen L, Ye Y, He G, Hua K, Jarjoura D, Nakano T, Ramesh GK, Shapiro CL, Barsky SH, Gao JX.
Int J Clin Exp Pathol. 2010 Mar 20;3(4):328-37.
PMID 20490325
 
Piwil2 suppresses p53 by inducing phosphorylation of signal transducer and activator of transcription 3 in tumor cells.
Lu Y, Zhang K, Li C, Yao Y, Tao D, Liu Y, Zhang S, Ma Y.
PLoS One. 2012;7(1):e30999. doi: 10.1371/journal.pone.0030999. Epub 2012 Jan 27.
PMID 22303479
 
Differential L1 regulation in pluripotent stem cells of humans and apes.
Marchetto MC, Narvaiza I, Denli AM, Benner C, Lazzarini TA, Nathanson JL, Paquola AC, Desai KN, Herai RH, Weitzman MD, Yeo GW, Muotri AR, Gage FH.
Nature. 2013 Nov 28;503(7477):525-9. doi: 10.1038/nature12686. Epub 2013 Oct 23.
PMID 24153179
 
Absence of PIWIL2 (HILI) expression in human bladder cancer cell lines and tissues.
Nikpour P, Forouzandeh-Moghaddam M, Ziaee SA, Dokun OY, Schulz WA, Mowla SJ.
Cancer Epidemiol. 2009 Oct;33(3-4):271-5. doi: 10.1016/j.canep.2009.06.011. Epub 2009 Jul 30.
PMID 19683485
 
Clinicopathologic Implications of PIWIL2 Expression in Colorectal Cancer.
Oh SJ, Kim SM, Kim YO, Chang HK.
Korean J Pathol. 2012 Aug;46(4):318-23. doi: 10.4132/KoreanJPathol.2012.46.4.318. Epub 2012 Aug 23.
PMID 23110023
 
Global gene expression analysis in fetal mouse ovaries with and without meiosis and comparison of selected genes with meiosis in the testis.
Olesen C, Nyeng P, Kalisz M, Jensen TH, Moller M, Tommerup N, Byskov AG.
Cell Tissue Res. 2007 Apr;328(1):207-21. Epub 2006 Nov 25.
PMID 17431699
 
Complete sequencing and characterization of 21,243 full-length human cDNAs.
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S.
Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21.
PMID 14702039
 
Argonaute: A scaffold for the function of short regulatory RNAs.
Parker JS, Barford D.
Trends Biochem Sci. 2006 Nov;31(11):622-30. Epub 2006 Oct 6. (REVIEW)
PMID 17029813
 
Beyond transposons: the epigenetic and somatic functions of the Piwi-piRNA mechanism.
Peng JC, Lin H.
Curr Opin Cell Biol. 2013 Apr;25(2):190-4. doi: 10.1016/j.ceb.2013.01.010. Epub 2013 Mar 4. (REVIEW)
PMID 23465540
 
Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas.
Qiao D, Zeeman AM, Deng W, Looijenga LH, Lin H.
Oncogene. 2002 Jun 6;21(25):3988-99.
PMID 12037681
 
Identification of eight members of the Argonaute family in the human genome.
Sasaki T, Shiohama A, Minoshima S, Shimizu N.
Genomics. 2003 Sep;82(3):323-30.
PMID 12906857
 
SMART, a simple modular architecture research tool: identification of signaling domains.
Schultz J, Milpetz F, Bork P, Ponting CP.
Proc Natl Acad Sci U S A. 1998 May 26;95(11):5857-64.
PMID 9600884
 
A novel in vitro model for cancer stem cell culture using ectopically expressed piwil2 stable cell line.
Shahali M, Kabir-Salmani M, Nayernia K, Soleimanpour-Lichaei HR, Vasei M, Mowla SJ, Ranaie E, Shakibaie M, Modaresi MH.
Cell J. 2013 Fall;15(3):250-7. Epub 2013 Aug 24.
PMID 24027667
 
Epigenetics-related genes in prostate cancer: expression profile in prostate cancer tissues, androgen-sensitive and -insensitive cell lines.
Shaikhibrahim Z, Lindstrot A, Ochsenfahrt J, Fuchs K, Wernert N.
Int J Mol Med. 2013 Jan;31(1):21-5. doi: 10.3892/ijmm.2012.1173. Epub 2012 Nov 6.
PMID 23135352
 
The crystal structure of the Argonaute2 PAZ domain reveals an RNA binding motif in RNAi effector complexes.
Song JJ, Liu J, Tolia NH, Schneiderman J, Smith SK, Martienssen RA, Hannon GJ, Joshua-Tor L.
Nat Struct Biol. 2003 Dec;10(12):1026-32. Epub 2003 Nov 16.
PMID 14625589
 
Crystal structure of Argonaute and its implications for RISC slicer activity.
Song JJ, Smith SK, Hannon GJ, Joshua-Tor L.
Science. 2004 Sep 3;305(5689):1434-7. Epub 2004 Jul 29.
PMID 15284453
 
PIWI Expression and Function in Cancer.
Suzuki R, Honda S, Kirino Y.
Front Genet. 2012 Oct 16;3:204. doi: 10.3389/fgene.2012.00204. eCollection 2012.
PMID 23087701
 
MILI, a PIWI-interacting RNA-binding protein, is required for germ line stem cell self-renewal and appears to positively regulate translation.
Unhavaithaya Y, Hao Y, Beyret E, Yin H, Kuramochi-Miyagawa S, Nakano T, Lin H.
J Biol Chem. 2009 Mar 6;284(10):6507-19. doi: 10.1074/jbc.M809104200. Epub 2008 Dec 29.
PMID 19114715
 
Proteomic analysis of murine Piwi proteins reveals a role for arginine methylation in specifying interaction with Tudor family members.
Vagin VV, Wohlschlegel J, Qu J, Jonsson Z, Huang X, Chuma S, Girard A, Sachidanandam R, Hannon GJ, Aravin AA.
Genes Dev. 2009 Aug 1;23(15):1749-62. doi: 10.1101/gad.1814809. Epub 2009 Jul 7.
PMID 19584108
 
Mili interacts with tudor domain-containing protein 1 in regulating spermatogenesis.
Wang J, Saxe JP, Tanaka T, Chuma S, Lin H.
Curr Biol. 2009 Apr 28;19(8):640-4. doi: 10.1016/j.cub.2009.02.061. Epub 2009 Apr 2.
PMID 19345100
 
An abundance of X-linked genes expressed in spermatogonia.
Wang PJ, McCarrey JR, Yang F, Page DC.
Nat Genet. 2001 Apr;27(4):422-6.
PMID 11279525
 
The PIWI protein acts as a predictive marker for human gastric cancer.
Wang Y, Liu Y, Shen X, Zhang X, Chen X, Yang C, Gao H.
Int J Clin Exp Pathol. 2012;5(4):315-25. Epub 2012 Apr 19.
PMID 22670175
 
Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus.
Watanabe T, Tomizawa S, Mitsuya K, Totoki Y, Yamamoto Y, Kuramochi-Miyagawa S, Iida N, Hoki Y, Murphy PJ, Toyoda A, Gotoh K, Hiura H, Arima T, Fujiyama A, Sado T, Shibata T, Nakano T, Lin H, Ichiyanagi K, Soloway PD, Sasaki H.
Science. 2011 May 13;332(6031):848-52. doi: 10.1126/science.1203919.
PMID 21566194
 
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Wu Q, Ma Q, Shehadeh LA, Wilson A, Xia L, Yu H, Webster KA.
Biochem Biophys Res Commun. 2010 Jun 11;396(4):915-20. doi: 10.1016/j.bbrc.2010.05.022. Epub 2010 May 10.
PMID 20460113
 
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Wu W, Choudhry H, Lu Y, Ma Y.
Next Generation Sequencing in Cancer Research (Springer New York); 2013, pp 217-231.
 
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Xu M, You Y, Hunsicker P, Hori T, Small C, Griswold MD, Hecht NB.
Biol Reprod. 2008 Jul;79(1):51-7. doi: 10.1095/biolreprod.108.068072. Epub 2008 Apr 9.
PMID 18401007
 
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Ye Y, Yin DT, Chen L, Zhou Q, Shen R, He G, Yan Q, Tong Z, Issekutz AC, Shapiro CL, Barsky SH, Lin H, Li JJ, Gao JX.
PLoS One. 2010 Oct 20;5(10):e13406. doi: 10.1371/journal.pone.0013406.
PMID 20975993
 
[Expression of Piwil2 and its relationship with tumor invasion and metastasis in papillary thyroid carcinoma].
Yin DT, Li HQ, Wang YF, Cao SL, Zhou YB, Zheng LY, Jiang JH, Wang QD.
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2011a Mar;46(3):237-9.
PMID 21575418
 
Germline stem cell gene PIWIL2 mediates DNA repair through relaxation of chromatin.
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PLoS One. 2011b;6(11):e27154. doi: 10.1371/journal.pone.0027154. Epub 2011 Nov 16.
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Citation

This paper should be referenced as such :
JX Gao, N Liu, HL Wu
PIWIL2 (piwi-like RNA-mediated gene silencing 2)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(12):919-927.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PIWIL2ID41724ch8p21.html


External links

Nomenclature
HGNC (Hugo)PIWIL2   17644
Cards
AtlasPIWIL2ID41724ch8p21
Entrez_Gene (NCBI)PIWIL2  55124  piwi like RNA-mediated gene silencing 2
AliasesCT80; HILI; PIWIL1L; mili
GeneCards (Weizmann)PIWIL2
Ensembl hg19 (Hinxton)ENSG00000197181 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000197181 [Gene_View]  chr8:22275567-22356071 [Contig_View]  PIWIL2 [Vega]
ICGC DataPortalENSG00000197181
TCGA cBioPortalPIWIL2
AceView (NCBI)PIWIL2
Genatlas (Paris)PIWIL2
WikiGenes55124
SOURCE (Princeton)PIWIL2
Genetics Home Reference (NIH)PIWIL2
Genomic and cartography
GoldenPath hg38 (UCSC)PIWIL2  -     chr8:22275567-22356071 +  8p21.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PIWIL2  -     8p21.3   [Description]    (hg19-Feb_2009)
EnsemblPIWIL2 - 8p21.3 [CytoView hg19]  PIWIL2 - 8p21.3 [CytoView hg38]
Mapping of homologs : NCBIPIWIL2 [Mapview hg19]  PIWIL2 [Mapview hg38]
OMIM610312   
Gene and transcription
Genbank (Entrez)AB079367 AK000397 AK001213 AK027497 AK056418
RefSeq transcript (Entrez)NM_001135721 NM_001330480 NM_018068
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PIWIL2
Cluster EST : UnigeneHs.614809 [ NCBI ]
CGAP (NCI)Hs.614809
Alternative Splicing GalleryENSG00000197181
Gene ExpressionPIWIL2 [ NCBI-GEO ]   PIWIL2 [ EBI - ARRAY_EXPRESS ]   PIWIL2 [ SEEK ]   PIWIL2 [ MEM ]
Gene Expression Viewer (FireBrowse)PIWIL2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)55124
GTEX Portal (Tissue expression)PIWIL2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8TC59   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8TC59  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8TC59
Splice isoforms : SwissVarQ8TC59
PhosPhoSitePlusQ8TC59
Domaine pattern : Prosite (Expaxy)PAZ (PS50821)    PIWI (PS50822)   
Domains : Interpro (EBI)ArgoL1    PAZ_dom    Piwi    RNaseH-like_dom   
Domain families : Pfam (Sanger)ArgoL1 (PF08699)    PAZ (PF02170)    Piwi (PF02171)   
Domain families : Pfam (NCBI)pfam08699    pfam02170    pfam02171   
Domain families : Smart (EMBL)DUF1785 (SM01163)  PAZ (SM00949)  Piwi (SM00950)  
Conserved Domain (NCBI)PIWIL2
DMDM Disease mutations55124
Blocks (Seattle)PIWIL2
PDB (SRS)3O7X    3QIR   
PDB (PDBSum)3O7X    3QIR   
PDB (IMB)3O7X    3QIR   
PDB (RSDB)3O7X    3QIR   
Structural Biology KnowledgeBase3O7X    3QIR   
SCOP (Structural Classification of Proteins)3O7X    3QIR   
CATH (Classification of proteins structures)3O7X    3QIR   
SuperfamilyQ8TC59
Human Protein AtlasENSG00000197181
Peptide AtlasQ8TC59
HPRD11434
IPIIPI00154664   IPI00923514   
Protein Interaction databases
DIP (DOE-UCLA)Q8TC59
IntAct (EBI)Q8TC59
FunCoupENSG00000197181
BioGRIDPIWIL2
STRING (EMBL)PIWIL2
ZODIACPIWIL2
Ontologies - Pathways
QuickGOQ8TC59
Ontology : AmiGORNA 5'-end processing  mRNA binding  endoribonuclease activity  cytoplasm  polysome  multicellular organism development  spermatogenesis  perinucleolar chromocenter  negative regulation of transposition  germ-line stem cell population maintenance  gene silencing by RNA  chromatoid body  piRNA binding  piRNA binding  piRNA metabolic process  DNA methylation involved in gamete generation  P granule  positive regulation of translation  metal ion binding  oogenesis  meiotic cell cycle  positive regulation of meiosis I  positive regulation of histone H3-K14 acetylation  pi-body  RNA phosphodiester bond hydrolysis, endonucleolytic  dense body  PET complex  positive regulation of histone H3-K9 acetylation  
Ontology : EGO-EBIRNA 5'-end processing  mRNA binding  endoribonuclease activity  cytoplasm  polysome  multicellular organism development  spermatogenesis  perinucleolar chromocenter  negative regulation of transposition  germ-line stem cell population maintenance  gene silencing by RNA  chromatoid body  piRNA binding  piRNA binding  piRNA metabolic process  DNA methylation involved in gamete generation  P granule  positive regulation of translation  metal ion binding  oogenesis  meiotic cell cycle  positive regulation of meiosis I  positive regulation of histone H3-K14 acetylation  pi-body  RNA phosphodiester bond hydrolysis, endonucleolytic  dense body  PET complex  positive regulation of histone H3-K9 acetylation  
Pathways : KEGGDorso-ventral axis formation   
REACTOMEQ8TC59 [protein]
REACTOME PathwaysR-HSA-5601884 [pathway]   
NDEx NetworkPIWIL2
Atlas of Cancer Signalling NetworkPIWIL2
Wikipedia pathwaysPIWIL2
Orthology - Evolution
OrthoDB55124
GeneTree (enSembl)ENSG00000197181
Phylogenetic Trees/Animal Genes : TreeFamPIWIL2
HOVERGENQ8TC59
HOGENOMQ8TC59
Homologs : HomoloGenePIWIL2
Homology/Alignments : Family Browser (UCSC)PIWIL2
Gene fusions - Rearrangements
Fusion : MitelmanPPP3CC/PIWIL2 [8p21.3/8p21.3]  [t(8;8)(p21;p21)]  
Fusion: TCGAPPP3CC 8p21.3 PIWIL2 8p21.3 HNSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPIWIL2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PIWIL2
dbVarPIWIL2
ClinVarPIWIL2
1000_GenomesPIWIL2 
Exome Variant ServerPIWIL2
ExAC (Exome Aggregation Consortium)PIWIL2 (select the gene name)
Genetic variants : HAPMAP55124
Genomic Variants (DGV)PIWIL2 [DGVbeta]
DECIPHERPIWIL2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPIWIL2 
Mutations
ICGC Data PortalPIWIL2 
TCGA Data PortalPIWIL2 
Broad Tumor PortalPIWIL2
OASIS PortalPIWIL2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPIWIL2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPIWIL2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PIWIL2
DgiDB (Drug Gene Interaction Database)PIWIL2
DoCM (Curated mutations)PIWIL2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PIWIL2 (select a term)
intoGenPIWIL2
NCG5 (London)PIWIL2
Cancer3DPIWIL2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM610312   
Orphanet
MedgenPIWIL2
Genetic Testing Registry PIWIL2
NextProtQ8TC59 [Medical]
TSGene55124
GENETestsPIWIL2
Target ValidationPIWIL2
Huge Navigator PIWIL2 [HugePedia]
snp3D : Map Gene to Disease55124
BioCentury BCIQPIWIL2
ClinGenPIWIL2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD55124
Chemical/Pharm GKB GenePA38461
Clinical trialPIWIL2
Miscellaneous
canSAR (ICR)PIWIL2 (select the gene name)
Probes
Litterature
PubMed36 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePIWIL2
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