BPIFA4P

Last updated
BPIFA4P
Identifiers
Aliases BPIFA4P , BASE, BPI fold containing family A member 4, pseudogene
External IDs OMIM: 607627 GeneCards: BPIFA4P
Orthologs
SpeciesHumanMouse
Entrez

317716

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Ensembl

ENSG00000183566

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UniProt

n
a

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RefSeq (mRNA)

NM_173859

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RefSeq (protein)

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Location (UCSC) Chr 20: 33.19 – 33.21 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

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. [3] [4] It is also known as Latherin in horse, encoded by the Lath/Bpifa4 gene but is somewhat divergent from the other species. [5] [6] [7] Latherin/BPIFA4 is a secreted protein found in saliva and sweat.

Contents

In humans, no functional protein expressed therefore BPIFB4P is referred to as a pseudogene . [7] [8] [9] 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). [10] [11]

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. [12] This superfamily is also known as the BPI/LBP/PLUNC family or the BPI/LPB/CETP family. [13] 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.

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 BPIFfamily-BPIF-A4P.png
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. [7] [14] 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, [7] [9] the RNA sequence for a wikt:putative protein has been detected at moderate levels in several glands (including salivary and mammillary), skin, and breast cancer. [15] [11] That pattern is consistent with the expression of normal BPIFA4/Latherin found in saliva and sweat of other species such as cow, [4] horse, [5] [6] and sheep. [16] 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. [6] 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:

"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." [17]

That non-functional protein came to be known as BASE (Breast cancer And Salivary gland Expression) protein. [11] 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. [11] [18] 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. [19] 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. [20] 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. [7] 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. [17] 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, [9] but Western blots show the protein migrates at a size larger than 22 kDa. [21] 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.

Related Research Articles

<span class="mw-page-title-main">Chromosome 20</span> Human chromosome

Chromosome 20 is one of the 23 pairs of chromosomes in humans. Chromosome 20 spans around 66 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells. Chromosome 20 was fully sequenced in 2001 and was reported to contain over 59 million base pairs. Since then, due to sequencing improvements and fixes, the length of chromosome 20 has been updated to just over 66 million base pairs.

<span class="mw-page-title-main">BPIFA1</span> Protein-coding gene in the species Homo sapiens

BPI fold containing family A, member 1 (BPIFA1), also known as Palate, lung, and nasal epithelium clone (PLUNC), is a protein that in humans is encoded by the BPIFA1 gene. It was also formerly known as "Secretory protein in upper respiratory tracts" (SPURT). The BPIFA1 gene sequence predicts 4 transcripts ; 3 mRNA variants have been well characterized. The resulting BPIFA1 is a secreted protein, expressed at very high levels in mucosa of the airways and salivary glands; at high levels in oropharyneal epithelium, including tongue and tonsils; and at moderate levels many other tissue types and glands including pituitary, testis, lung, bladder, blood, prostate, pancreas, levels in the digestive tract and pancreas. The protein can be detected on the apical side of epithelial cells and in airway surface liquid, nasal mucus, and sputum.

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<span class="mw-page-title-main">CST4</span> Protein-coding gene in humans

Cystatin-S is a protein that in humans is encoded by the CST4 gene.

<span class="mw-page-title-main">BPIFB2</span> Protein-coding gene in the species Homo sapiens

BPI fold-containing family B, member 2, (BPIFB2) also known as bactericidal/permeability-increasing protein-like 1, is a protein that in humans is encoded by the BPIFB2 gene.

<span class="mw-page-title-main">Lipid-binding serum glycoprotein</span>

In molecular biology, the lipid-binding serum glycoproteins family, also known as the BPI/LBP/Plunc family or LBP/BPI/CETP family represents a family which includes mammalian lipid-binding serum glycoproteins and/or proteins containing a structural motif known as the BPI fold. Members of this family include:

<span class="mw-page-title-main">BPIFA3</span> Protein-coding gene in the species Homo sapiens

BPI fold containing family A, member 3 (BPIFA3) is a protein that in humans is encoded by the BPIFA3 gene. The gene is also known as SPLUNC3 and C20orf71 in humans and the orthologous gene in mice is 1700058C13Rik. There are multiple variants of the BPIFA3 projected to be a secreted protein. It is very highly expressed in testis with little or no expression in other tissues. The Human Protein Atlas project and Mouse ENCODE Consortium report RNA-Seq expression at RPKM levels of 29.1 for human testis and 69.4 for mouse, but 0 for all other tissues. Similarly, the Bgee consortium, using multiple techniques in addition to RNA-Seq, reports a relative Expression Score of 95.8 out of 100 for testis and 99.0 for sperm in humans; however low levels of BPIFA3 between 20 and 30 were seen for a variety of tissues such as muscle, glands, prostate, nervous system, and skin.

<span class="mw-page-title-main">CZIB</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">BPIFB4</span> Protein-coding gene in the species Homo sapiens

BPI fold containing family B, member 4 (BPIFB4) is a protein that in humans is encoded by the BPIFB4 gene. It was formerly known as "Long palate, lung and nasal epithelium carcinoma-associated protein 4" encoded by the LPLUNC4 gene. The BPIFB4 gene sequence predicts 4 transcripts ; 3 isoforms have been well characterized. In a variety of mammals, BPIFB4 is generally expressed in very high levels in the olfactory epithelium, high levels in the gonads and pituitary, moderate levels in white blood cells (monocytes) It can occur either localized in the cytoplasm of cells or secreted and circulated systemically in blood plasma.

<span class="mw-page-title-main">Transmembrane protein 151b</span> Transmembrane protein

Transmembrane protein 151B is a protein that in humans is encoded by the TMEM151B gene.

<span class="mw-page-title-main">BPIFB1</span> Protein-coding gene in the species Homo sapiens

BPI fold-containing family B member 1 (BPIFB1) is a protein that in humans is encoded by the BPIFB1 gene. BPIFB1 is a secreted protein, expressed at very high levels in mucosa of the airways and salivary glands, and at moderate levels in the digestive tract and pancreas.

<span class="mw-page-title-main">Chromosome 9 open reading frame 43</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">C7orf26</span> Human protein-encoding gene on chromosome 7

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<span class="mw-page-title-main">FAM227B</span> Protein-coding gene in the species Homo sapiens

FAM227B is a protein that in humans is encoded by FAM227B gene. FAM227B stands for family with sequence similarity 227 member B and encodes protein FAM227B of the same name. Its aliases include C15orf33, MGC57432 and FLJ23800.

<span class="mw-page-title-main">C17orf75</span> Protein-coding gene in the species Homo sapiens

Chromosome 17 open reading frame 75 is a protein that in humans is encoded by the C17orf75 gene. C17orf75 is also known as SRI2 and is a human protein encoding gene located at 17q11.2 on the complementary strand. The protein this gene encodes is also known as NJMU-R1. The C17orf75 gene is ubiquitously expressed at medium-low levels throughout the body and at slightly higher levels in the brain and testes. This protein is thought to be part of a complex associated with golgin-mediated vesicle capture.

<span class="mw-page-title-main">BPIFB3</span> Protein-coding gene in the species Homo sapiens

BPI fold containing family B, member 3 (BPIFB3) is a protein that in humans is encoded by the BPIFB3 gene. Two variants have been detected in humans.

<span class="mw-page-title-main">BPIFB5P</span> Pseudogene in the species Homo sapiens

BPI fold containing family B, member 5 is a non-human protein encoded by the Bpifb5 gene, also known as Lplunc5. The BPIFB5 protein and Bpifb5 gene have been characterized in mammals such as rodents and even-toed ungulates but are apparently lacking in primates and other vertebrates such as birds, reptiles, and amphibians. The protein in rodents is expressed at moderately high levels in mucosa of the airways and at moderate levels in salivary glands, esophagus, and gonads ; in even-toed ungulates expression is high in testis, moderate in brain and striated muscle, and low in kidney.

<span class="mw-page-title-main">BPIFB6</span> Protein-coding gene in the species Homo sapiens

BPI fold containing family B, member 6 (BPIFB6), also known as bactericidal/permeability-increasing protein-like 3 (BPIL3), is a protein that in humans is encoded by the BPIFB6 gene, also known as BPIL3 and LPLUNC6. It is expressed at high levels in hypertrophic tonsils, at relatively moderate levels in oronasal epithelium including nasal mucosa, tongue, and salivary gland, as well as esophageal mucosa at lesser levels. Orthologs are present in many vertebrate species including mammals, birds, reptiles, and amphibians.

<span class="mw-page-title-main">BPIFB9P</span> Pseudogene in the species Homo sapiens

Vomeromodulin is a non-human protein also known as BPI fold containing family B, member 9 (BPIFB9) in the rat encoded by the Bpifb9/RYF3 gene, and as BPI fold containing family B, member 9A (BPIFB9A) encoded by the Bpifb9a gene in the mouse. This protein has been characterized in mammals such as rodents, carnivores, even-toed ungulates, insectivores, bats, lagomorphs, and shrews but is apparently absent in primates and other vertebrates such as birds, reptiles, and amphibians. Its function is associated with detection of chemical odorant pheromone molecules.

<span class="mw-page-title-main">BPIFA2</span> Protein-coding gene in the species Homo sapiens

BPI fold containing family A, member 2 (BPIFA2), also known as Parotid Secretory Protein (PSP), is a protein that in humans is encoded by the BPIFA2 gene. The BPIFA2 gene sequence predicts multiple transcripts ; 2 mRNA variants have been well characterized. The resulting BPIFA2 is a secreted protein, expressed at very high levels in the parotid (salivary) gland; at high levels in oropharyngeal mucosa, including tongue; and at moderate levels many other tissue types and glands including mammary gland, testis, lung, bladder, blood, prostate, adrenal gland, kidney, and pancreas.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000183566 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ "BPIFA4 BPI fold containing family A, member 4 [Macaca mulatta (Rhesus monkey)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 18 February 2023.
  4. 1 2 "BPIFA4 BPI fold containing family A, member 4 [Bos taurus (cattle)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 18 February 2023.
  5. 1 2 "LATH latherin [Equus caballus (horse)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 18 February 2023.
  6. 1 2 3 McDonald RE, Fleming RI, Beeley JG, Bovell DL, Lu JR, Zhao X, et al. (May 2009). "Latherin: a surfactant protein of horse sweat and saliva". PLOS ONE. 4 (5): e5726. Bibcode:2009PLoSO...4.5726M. doi: 10.1371/journal.pone.0005726 . PMC   2684629 . PMID   19478940.
  7. 1 2 3 4 5 Bingle CD, Seal RL, Craven CJ (August 2011). "Systematic nomenclature for the PLUNC/PSP/BSP30/SMGB proteins as a subfamily of the BPI fold-containing superfamily". Biochemical Society Transactions. 39 (4): 977–983. doi:10.1042/BST0390977. PMC   3196848 . PMID   21787333.
  8. ↑ "BPIFA4P BPI fold containing family A member 4, pseudogene [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 18 February 2023.
  9. 1 2 3 "Homo sapiens BPI fold containing family A member 4, pseudogene (BPIFA4P), non-coding RNA". 29 March 2021. Retrieved 18 February 2023. Accession NR_026760
  10. ↑ "Q86YQ2 - LATH_HUMAN". www.uniprot.org. Retrieved 18 February 2023.
  11. 1 2 3 4 Egland KA, Vincent JJ, Strausberg R, Lee B, Pastan I (February 2003). "Discovery of the breast cancer gene BASE using a molecular approach to enrich for genes encoding membrane and secreted proteins". Proceedings of the National Academy of Sciences of the United States of America. 100 (3): 1099–1104. Bibcode:2003PNAS..100.1099E. doi: 10.1073/pnas.0337425100 . PMC   298733 . PMID   12538848.
  12. ↑ Beamer LJ, Carroll SF, Eisenberg D (April 1998). "The BPI/LBP family of proteins: a structural analysis of conserved regions". Protein Science. 7 (4): 906–914. doi:10.1002/pro.5560070408. PMC   2143972 . PMID   9568897.
  13. ↑ "CDD Conserved Protein Domain Family: BPI". www.ncbi.nlm.nih.gov.
  14. ↑ Beamer LJ, Fischer D, Eisenberg D (July 1998). "Detecting distant relatives of mammalian LPS-binding and lipid transport proteins". Protein Science. 7 (7): 1643–1646. doi:10.1002/pro.5560070721. PMC   2144061 . PMID   9684900.
  15. ↑ "Gene : BPIFA4P - ENSG00000183566". bgee.org. The Bgee suite: integrated curated expression atlas and comparative transcriptomics in animals. Retrieved 17 February 2023.
  16. ↑ "Gene : LOC101116500 - ENSOARG00000006525 - Ovis aries (Sheep)". bgee.org. The Bgee suite: integrated curated expression atlas and comparative transcriptomics in animals. Retrieved 17 February 2023.
  17. 1 2 Bingle CD, Bingle L, Craven CJ (August 2011). "Distant cousins: genomic and sequence diversity within the BPI fold-containing (BPIF)/PLUNC protein family". Biochemical Society Transactions. 39 (4): 961–965. doi:10.1042/BST0390961. PMID   21787330.
  18. ↑ Vargas PA, Speight PM, Bingle CD, Barrett AW, Bingle L (October 2008). "Expression of PLUNC family members in benign and malignant salivary gland tumours". Oral Diseases. 14 (7): 613–619. doi:10.1111/j.1601-0825.2007.01429.x. PMC   2853704 . PMID   18221458.
  19. ↑ Bretschneider N, Brand H, Miller N, Lowery AJ, Kerin MJ, Gannon F, Denger S (January 2008). "Estrogen induces repression of the breast cancer and salivary gland expression gene in an estrogen receptor alpha-dependent manner". Cancer Research. 68 (1): 106–114. doi: 10.1158/0008-5472.CAN-07-5647 . PMID   18172302.
  20. ↑ Bernardo GM, Keri RA (April 2012). "FOXA1: a transcription factor with parallel functions in development and cancer". Bioscience Reports. 32 (2): 113–130. doi:10.1042/BSR20110046. PMC   7025859 . PMID   22115363.
  21. ↑ "BASE (Q-15): sc-85291" (PDF). www.scbt.com. Santa Cruz Biotechnology, Inc. Archived from the original (PDF) on 20 Mar 2023. Retrieved 20 March 2023.
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