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Pharmacogenetics of human ABC transporter ABCC11: new insights into apocrine gland growth and metabolite secretion.

Ishikawa T, Toyoda Y, Yoshiura K, Niikawa N - Front Genet (2013)

Bottom Line: Cell secretion is an important physiological process that ensures smooth metabolic activities and tissue repair as well as growth and immunological functions in the body.The wild-type (Gly180) of ABCC11 is associated with wet-type earwax, axillary osmidrosis, and colostrum secretion from the mammary gland as well as the potential risk of mastopathy.Furthermore, the SNP (538G > A) in the ABCC11 gene is suggested to be a clinical biomarker for the prediction of chemotherapeutic efficacy.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology Yokohama, Japan ; Omics Science Center, RIKEN Yokohama Institute Yokohama, Japan.

ABSTRACT
Cell secretion is an important physiological process that ensures smooth metabolic activities and tissue repair as well as growth and immunological functions in the body. Apocrine secretion occurs when the secretory process is accomplished with a partial loss of cell cytoplasm. The secretory materials are contained within secretory vesicles and are released during secretion as cytoplasmic fragments into the glandular lumen or interstitial space. The recent finding that the non-synonymous single nucleotide polymorphisms (SNP) 538G > A (rs17822931; Gly180Arg) in the ABCC11 gene determines the type of earwax in humans has shed light on the novel function of this ABC (ATP-binding cassette) transporter in apocrine glands. The wild-type (Gly180) of ABCC11 is associated with wet-type earwax, axillary osmidrosis, and colostrum secretion from the mammary gland as well as the potential risk of mastopathy. Furthermore, the SNP (538G > A) in the ABCC11 gene is suggested to be a clinical biomarker for the prediction of chemotherapeutic efficacy. The aim of this review article is to provide an overview on the discovery and characterization of genetic polymorphisms in the human ABCC11 gene and to explain the impact of ABCC11 538G > A on the apocrine phenotype as well as the anthropological aspect of this SNP in the ABCC11 gene and patients' response to nucleoside-based chemotherapy.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of intracellular sorting of ABCC11 WT and proteasomal degradation of the R180 (Arg180) variant in secretory cells of the apocrine gland. De novo synthesized ABCC11 WT is N-linked glycosylated at Asn838 and Asn844 in the ER, further processed in the Golgi apparatus, and destined for the membranes of intracellular granules and vacuoles. Ceruminous components are thought to be transported by ABCC11 WT and sequestered in intracellular granules and vacuoles. SNP variant R180 lacking N-linked glycosylation is recognized as a misfolded protein in the ER and readily undergoes ubiquitination and proteasomal degradation (ERAD pathway). ER, endoplasmic reticulum; ERAD, ER-associated degradation. This scheme is modified from Toyoda et al. (2009).
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Figure 4: Schematic illustration of intracellular sorting of ABCC11 WT and proteasomal degradation of the R180 (Arg180) variant in secretory cells of the apocrine gland. De novo synthesized ABCC11 WT is N-linked glycosylated at Asn838 and Asn844 in the ER, further processed in the Golgi apparatus, and destined for the membranes of intracellular granules and vacuoles. Ceruminous components are thought to be transported by ABCC11 WT and sequestered in intracellular granules and vacuoles. SNP variant R180 lacking N-linked glycosylation is recognized as a misfolded protein in the ER and readily undergoes ubiquitination and proteasomal degradation (ERAD pathway). ER, endoplasmic reticulum; ERAD, ER-associated degradation. This scheme is modified from Toyoda et al. (2009).

Mentions: The endoplasmic reticulum (ER) and Golgi apparatus are the synthesis and maturation sites of proteins destined for the plasma membrane, the secretory and endocytic organelles, and secretion (Ellgaard et al., 1999; Helenius and Aebi, 2004). Efficient quality control systems have evolved to prevent incompletely folded proteins from moving along the secretory pathway. Accumulation of misfolded proteins in the ER would detrimentally affect cellular functions. Therefore, misfolded proteins may be removed from the ER by retrotranslocation to the cytosol compartment where they are degraded by the ubiquitin-proteasome system. This process is known as ER-associated degradation (ERAD; Mori, 2000; Ellgaard and Helenius, 2001; Hampton, 2002; Kleizen and Braakman, 2004). It is likely that the product of the SNP variant (Arg180) is recognized as a misfolded protein in the ER and readily undergoes proteasomal degradation. An electrostatic charge (either positive or negative) at amino acid 180 in the transmembrane domain 1 (TM1) might interfere with correct folding of the de novo synthesized ABCC11 protein in the ER (Toyoda et al., 2009). This ERAD processing of the SNP variant (Arg180) of ABCC11 may greatly influence the activity of ceruminous apocrine glands and determine the type of human earwax. Similar ERAD processing is considered to take place for the SNP variant (Arg180) of ABCC11 in axillary and mammary apocrine glands. Figure 4 schematically illustrates the impact of this SNP on the cellular localization and function of ABCC11 in secretory cells of the apocrine gland. Asn838 and Asn844 are glycosylation target sites in the human ABCC11. The N-linked glycans are thought to be subjected to extensive modification as glycoproteins mature and move through the ER via the Golgi apparatus to their final destinations as, for example, intracellular granules and large vacuoles of secretory cells in the apocrine gland.


Pharmacogenetics of human ABC transporter ABCC11: new insights into apocrine gland growth and metabolite secretion.

Ishikawa T, Toyoda Y, Yoshiura K, Niikawa N - Front Genet (2013)

Schematic illustration of intracellular sorting of ABCC11 WT and proteasomal degradation of the R180 (Arg180) variant in secretory cells of the apocrine gland. De novo synthesized ABCC11 WT is N-linked glycosylated at Asn838 and Asn844 in the ER, further processed in the Golgi apparatus, and destined for the membranes of intracellular granules and vacuoles. Ceruminous components are thought to be transported by ABCC11 WT and sequestered in intracellular granules and vacuoles. SNP variant R180 lacking N-linked glycosylation is recognized as a misfolded protein in the ER and readily undergoes ubiquitination and proteasomal degradation (ERAD pathway). ER, endoplasmic reticulum; ERAD, ER-associated degradation. This scheme is modified from Toyoda et al. (2009).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539816&req=5

Figure 4: Schematic illustration of intracellular sorting of ABCC11 WT and proteasomal degradation of the R180 (Arg180) variant in secretory cells of the apocrine gland. De novo synthesized ABCC11 WT is N-linked glycosylated at Asn838 and Asn844 in the ER, further processed in the Golgi apparatus, and destined for the membranes of intracellular granules and vacuoles. Ceruminous components are thought to be transported by ABCC11 WT and sequestered in intracellular granules and vacuoles. SNP variant R180 lacking N-linked glycosylation is recognized as a misfolded protein in the ER and readily undergoes ubiquitination and proteasomal degradation (ERAD pathway). ER, endoplasmic reticulum; ERAD, ER-associated degradation. This scheme is modified from Toyoda et al. (2009).
Mentions: The endoplasmic reticulum (ER) and Golgi apparatus are the synthesis and maturation sites of proteins destined for the plasma membrane, the secretory and endocytic organelles, and secretion (Ellgaard et al., 1999; Helenius and Aebi, 2004). Efficient quality control systems have evolved to prevent incompletely folded proteins from moving along the secretory pathway. Accumulation of misfolded proteins in the ER would detrimentally affect cellular functions. Therefore, misfolded proteins may be removed from the ER by retrotranslocation to the cytosol compartment where they are degraded by the ubiquitin-proteasome system. This process is known as ER-associated degradation (ERAD; Mori, 2000; Ellgaard and Helenius, 2001; Hampton, 2002; Kleizen and Braakman, 2004). It is likely that the product of the SNP variant (Arg180) is recognized as a misfolded protein in the ER and readily undergoes proteasomal degradation. An electrostatic charge (either positive or negative) at amino acid 180 in the transmembrane domain 1 (TM1) might interfere with correct folding of the de novo synthesized ABCC11 protein in the ER (Toyoda et al., 2009). This ERAD processing of the SNP variant (Arg180) of ABCC11 may greatly influence the activity of ceruminous apocrine glands and determine the type of human earwax. Similar ERAD processing is considered to take place for the SNP variant (Arg180) of ABCC11 in axillary and mammary apocrine glands. Figure 4 schematically illustrates the impact of this SNP on the cellular localization and function of ABCC11 in secretory cells of the apocrine gland. Asn838 and Asn844 are glycosylation target sites in the human ABCC11. The N-linked glycans are thought to be subjected to extensive modification as glycoproteins mature and move through the ER via the Golgi apparatus to their final destinations as, for example, intracellular granules and large vacuoles of secretory cells in the apocrine gland.

Bottom Line: Cell secretion is an important physiological process that ensures smooth metabolic activities and tissue repair as well as growth and immunological functions in the body.The wild-type (Gly180) of ABCC11 is associated with wet-type earwax, axillary osmidrosis, and colostrum secretion from the mammary gland as well as the potential risk of mastopathy.Furthermore, the SNP (538G > A) in the ABCC11 gene is suggested to be a clinical biomarker for the prediction of chemotherapeutic efficacy.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology Yokohama, Japan ; Omics Science Center, RIKEN Yokohama Institute Yokohama, Japan.

ABSTRACT
Cell secretion is an important physiological process that ensures smooth metabolic activities and tissue repair as well as growth and immunological functions in the body. Apocrine secretion occurs when the secretory process is accomplished with a partial loss of cell cytoplasm. The secretory materials are contained within secretory vesicles and are released during secretion as cytoplasmic fragments into the glandular lumen or interstitial space. The recent finding that the non-synonymous single nucleotide polymorphisms (SNP) 538G > A (rs17822931; Gly180Arg) in the ABCC11 gene determines the type of earwax in humans has shed light on the novel function of this ABC (ATP-binding cassette) transporter in apocrine glands. The wild-type (Gly180) of ABCC11 is associated with wet-type earwax, axillary osmidrosis, and colostrum secretion from the mammary gland as well as the potential risk of mastopathy. Furthermore, the SNP (538G > A) in the ABCC11 gene is suggested to be a clinical biomarker for the prediction of chemotherapeutic efficacy. The aim of this review article is to provide an overview on the discovery and characterization of genetic polymorphisms in the human ABCC11 gene and to explain the impact of ABCC11 538G > A on the apocrine phenotype as well as the anthropological aspect of this SNP in the ABCC11 gene and patients' response to nucleoside-based chemotherapy.

No MeSH data available.


Related in: MedlinePlus