BPIFA4P

'''BPI fold containing family A, member 4''' (BPIFA4) is a non-human protein encoded by the ''Bpifa4'' gene in mammals such as monkey, cat, and cow but does not appear in rodents and humans.<ref name="Bpia4-Monkey">{{cite web |title=BPIFA4 BPI fold containing family A, member 4 [Macaca mulatta (Rhesus monkey)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/688385 |website=www.ncbi.nlm.nih.gov |access-date=18 February 2023}}</ref><ref name="Bpia4-Cow">{{cite web |title=BPIFA4 BPI fold containing family A, member 4 [Bos taurus (cattle)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/518904 |website=www.ncbi.nlm.nih.gov |access-date=18 February 2023}}</ref> It is also known as '''Latherin''' in horse, encoded by the ''Lath/Bpifa4'' gene but is somewhat divergent from the other species.<ref name="Bpifa4(Lath)-Horse">{{cite web |title=LATH latherin [Equus caballus (horse)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/100033921 |website=www.ncbi.nlm.nih.gov |access-date=18 February 2023}}</ref><ref name="McDonald-2009">{{cite journal | vauthors = McDonald RE, Fleming RI, Beeley JG, Bovell DL, Lu JR, Zhao X, Cooper A, Kennedy MW | display-authors = 6 | title = Latherin: a surfactant protein of horse sweat and saliva | journal = PLOS ONE | volume = 4 | issue = 5 | article-number = e5726 | date = May 2009 | pmid = 19478940 | pmc = 2684629 | doi = 10.1371/journal.pone.0005726 | doi-access = free | bibcode = 2009PLoSO...4.5726M }}</ref><ref name="Bingle-2011">{{cite journal | vauthors = Bingle CD, Seal RL, Craven CJ | title = Systematic nomenclature for the PLUNC/PSP/BSP30/SMGB proteins as a subfamily of the BPI fold-containing superfamily | journal = Biochemical Society Transactions | volume = 39 | issue = 4 | pages = 977–983 | date = August 2011 | pmid = 21787333 | pmc = 3196848 | doi = 10.1042/BST0390977 }}</ref> Latherin/BPIFA4 is a secreted protein found in saliva and sweat.

In humans, no functional protein is expressed, therefore '''''BPIFB4P''''' is referred to as a '''pseudogene'''.<ref name="Bingle-2011"/><ref name="BPIFA4P-Human">{{cite web |title=BPIFA4P BPI fold containing family A member 4, pseudogene [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/317716 |website=www.ncbi.nlm.nih.gov |access-date=18 February 2023}}</ref><ref name="BPIFA4P-RefSeq">{{cite web |title=Homo sapiens BPI fold containing family A member 4, pseudogene (BPIFA4P), non-coding RNA |url=https://www.ncbi.nlm.nih.gov/nuccore/NR_026760.1 |access-date=18 February 2023 |date=29 March 2021 |quote=Accession NR_026760}}</ref> However, a non-functional protein does appear; it known as '''BASE''' protein, secreted by breast cancer cell lines and salivary gland tissue (see section below).<ref name="BASE">{{cite web |title=Q86YQ2 - LATH_HUMAN |url=https://www.uniprot.org/uniprotkb/Q86YQ2/entry#names_and_taxonomy |website=www.uniprot.org |access-date=18 February 2023}}</ref><ref name="Egland-2003">{{cite journal | vauthors = Egland KA, Vincent JJ, Strausberg R, Lee B, Pastan I | title = Discovery of the breast cancer gene BASE using a molecular approach to enrich for genes encoding membrane and secreted proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 3 | pages = 1099–1104 | date = February 2003 | pmid = 12538848 | pmc = 298733 | doi = 10.1073/pnas.0337425100 | doi-access = free | bibcode = 2003PNAS..100.1099E }}</ref>

== Superfamily ==

BPIFA3 is a member of a BPI fold protein superfamily defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape.<ref name="Beamer-1998-A">{{cite journal | vauthors = Beamer LJ, Carroll SF, Eisenberg D | title = The BPI/LBP family of proteins: a structural analysis of conserved regions | journal = Protein Science | volume = 7 | issue = 4 | pages = 906–914 | date = April 1998 | pmid = 9568897 | pmc = 2143972 | doi = 10.1002/pro.5560070408 }}</ref> This superfamily is also known as the BPI/LBP/PLUNC family or the BPI/LPB/CETP family.<ref>{{cite web |title=CDD Conserved Protein Domain Family: BPI |url=https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=cl00188 |website=www.ncbi.nlm.nih.gov}}</ref> The BPI fold creates apolar binding pockets that can interact with hydrophobic and amphipathic molecules, such as the acyl carbon chains of lipopolysaccharide found on Gram-negative bacteria, but members of this family may have many other functions. thumb|left|BPIFA4P is a human pseudogene member the BPI-fold gene family and the transcribed protein in other species is a member of the BPI/LBP/PLUNC protein superfamily

Genes for the BPI/LBP/PLUNC superfamily are found in all vertebrate species, including distant homologs in non-vertebrate species such as insects, mollusks, and roundworms.<ref name="Bingle-2011"/><ref name="Beamer-1998-B">{{cite journal | vauthors = Beamer LJ, Fischer D, Eisenberg D | title = Detecting distant relatives of mammalian LPS-binding and lipid transport proteins | journal = Protein Science | volume = 7 | issue = 7 | pages = 1643–1646 | date = July 1998 | pmid = 9684900 | pmc = 2144061 | doi = 10.1002/pro.5560070721 }}</ref> Within that broad grouping is the BPIF gene family whose members encode the BPI fold structural motif and are found clustered on a single chromosome, e.g., Chromosome 20 in humans, Chromosome 2 in mouse, Chromosome 3 in rat, Chromosome 17 in pig, Chromosome 13 in cow. The BPIF gene family is split into two groupings, BPIFA and BPIFB. In humans, BIPFA consists of 3 protein encoding genes ''BPIFA1'', ''BPIFA2'', ''BPIFA3'', and 1 pseudogene ''BPIFA4P''; while BPIFB consists of 5 protein encoding genes ''BPIFB1'', ''BPIFB2'', ''BPIFB3'', ''BPIFB4'', ''BPIFB6'' and 2 pseudogenes ''BPIFB5P'', ''BPIFB9P''. What appears as pseudogenes in humans may appear as fully functional genes in other species.

== Function ==

Although ''BPIFA4P'' is identified as a pseudogene in humans,<ref name="Bingle-2011"/><ref name="BPIFA4P-RefSeq"/> the RNA sequence for a putative protein has been detected at moderate levels in several glands (including salivary and mammillary), skin, and breast cancer.<ref>{{cite web |title=Gene: BPIFA4P - ENSG00000183566 |url=https://bgee.org/gene/ENSG00000183566/ |website=bgee.org |publisher=The Bgee suite: integrated curated expression atlas and comparative transcriptomics in animals |access-date=17 February 2023}}</ref><ref name="Egland-2003"/> That pattern is consistent with the expression of normal BPIFA4/Latherin found in saliva and sweat of other species such as cow,<ref name="Bpia4-Cow"/> horse,<ref name="Bpifa4(Lath)-Horse"/><ref name="McDonald-2009"/> and sheep.<ref name="Sheep">{{cite web |title=Gene: LOC101116500 - ENSOARG00000006525 - Ovis aries (Sheep) |url=https://bgee.org/gene/ENSOARG00000006525/ |website=bgee.org |publisher=The Bgee suite: integrated curated expression atlas and comparative transcriptomics in animals |access-date=17 February 2023}}</ref> The function of BPIFA4 in those species is associated with BPIFA gene family members' properties of being a surfactant and binding to bacterial lipopolysaccharides. Sweat helps animals cool down, and in animals with pelts/fur BPIFA4/Latherin significantly reduces surface tension of sweat, acting as a wetting agent to facilitate evaporative cooling. Further, it is speculated that the presence of a surfactant protein in the saliva of ruminant animals (e.g., cow, horse, sheep) may assist in mastication of large quantities of vegetable matter in their diet.<ref name="McDonald-2009" /> BPIFA4 in saliva also may function as a first line of defense against bacteria, via bactericidal functions similar to other BIPFA and BIPFB family members.

=== BASE Protein ===

The expression of a pseudogene product in humans has caused unresolved issues about BPIFA4 in humans. This uncommon situation was summarized by Bingle and colleagues at University of Sheffield, who did extensive work on the BPI/LBP/PLUNC family: {{Blockquote|text="Human ''BPIFA4'' appears to be an example of a pseudogene (and should be properly identified as ''BPIFA4P'') that is perhaps better described as a 'dying' gene, since it appears to be both transcribed and translated, but no longer encodes a functional protein product."<ref name="Bingle-2011-2">{{cite journal | vauthors = Bingle CD, Bingle L, Craven CJ | title = Distant cousins: genomic and sequence diversity within the BPI fold-containing (BPIF)/PLUNC protein family | journal = Biochemical Society Transactions | volume = 39 | issue = 4 | pages = 961–965 | date = August 2011 | pmid = 21787330 | doi = 10.1042/BST0390961 }}</ref>}}

That non-functional protein came to be known as BASE ('''''B'''''reast cancer '''''A'''''nd '''''S'''''alivary gland '''''E'''''xpression) protein.<ref name="Egland-2003"/> Using a screening method for identifying human genes that code for membrane proteins, researchers at the National Cancer Institute discovered in 2003 a previously uncharacterized gene in breast cancer cell lines. With RT-PCR and Northern blot techniques, they detected the expression of BASE RNA in several breast cancer cell lines but not normal breast tissue. Separately BASE RNA expression was found in salivary gland tumors and normal salivary gland tissue.<ref name="Egland-2003"/><ref name="Vargas-2008">{{cite journal | vauthors = Vargas PA, Speight PM, Bingle CD, Barrett AW, Bingle L | title = Expression of PLUNC family members in benign and malignant salivary gland tumours | journal = Oral Diseases | volume = 14 | issue = 7 | pages = 613–619 | date = October 2008 | pmid = 18221458 | pmc = 2853704 | doi = 10.1111/j.1601-0825.2007.01429.x }}</ref> Thus the acronym was devised to reflect that pattern. Investigators at EMBL subsequently confirmed BASE/BPIFA4P expression in ~50% of actual breast cancer tumor samples they tested.<ref name="Brets-2008">{{cite journal | vauthors = Bretschneider N, Brand H, Miller N, Lowery AJ, Kerin MJ, Gannon F, Denger S | title = Estrogen induces repression of the breast cancer and salivary gland expression gene in an estrogen receptor alpha-dependent manner | journal = Cancer Research | volume = 68 | issue = 1 | pages = 106–114 | date = January 2008 | pmid = 18172302 | doi = 10.1158/0008-5472.CAN-07-5647 | url = https://figshare.com/articles/journal_contribution/22370891 | doi-access = free }}</ref> In particular, BASE/BPIFA4P expression was present in tumors with high levels of ERα estrogen receptor but not in tumors with low ERα. However, it was shown experimentally that estrogen represses the expression of the BASE/BPIFA4P gene, while the transcription factor FOXA1 activates the expression of BASE/BPIFA4P. The undetermined interplay between ERα and FOXA1 is likely to be important in hormone receptor-positive disease and acquired anti-hormone resistance.<ref name="Bernardo-2012">{{cite journal | vauthors = Bernardo GM, Keri RA | title = FOXA1: a transcription factor with parallel functions in development and cancer | journal = Bioscience Reports | volume = 32 | issue = 2 | pages = 113–130 | date = April 2012 | pmid = 22115363 | pmc = 7025859 | doi = 10.1042/BSR20110046 }}</ref> Although the BASE protein's potential function was never investigated, the presence of the BASE/BPIFA4P gene was nevertheless considered a potentially useful marker for breast cancer screening.

The ''BASE'' gene deposited into US and European databases was eventually recognized as being a member of the BPI/LBP/PLUNC family and subsequently relabeled as ''BPIFA4P''.<ref name="Bingle-2011"/> It was further recognized that unlike other primate genes for BPIFA4, the human ''BASE/BPIFA4P'' gene was missing a single nucleotide in exon 6. That deletion causes a frameshift mutation which results in a "premature" stop codon.<ref name="Bingle-2011-2"/> The resulting human BASE protein is much shorter than the functional BPIFA4 and Latherin proteins of other species. The original analysis predicted the BASE protein to be 19.5 kDa in size,<ref name="BPIFA4P-RefSeq"/> but Western blots show the protein migrates at a size larger than 22 kDa.<ref>{{cite web |title=BASE (Q-15): sc-85291 |url=https://datasheets.scbt.com/sc-85291.pdf |website=www.scbt.com |publisher=Santa Cruz Biotechnology, Inc. |access-date=20 March 2023 |archive-url=https://web.archive.org/web/20230320092112/https://datasheets.scbt.com/sc-85291.pdf |archive-date=20 Mar 2023}}</ref> This truncated human BASE protein lacks key structural elements of a functional BPIFA4 protein, namely a long α-helical segment that creates the BPI fold. Without that, BASE cannot function like any other BPI/LBP/PLUNC family member and is thus considered functionless.

== References == {{reflist}}

== External links == * {{UCSC gene info|BPIFA4P}}

Category:Pseudogenes Category:Genes on human chromosome 20