Oligopeptide transportation is mediated by the peptide transporter (PepT), which consists of two isoforms, PepT1 and PepT2. Because PepT play essential roles in amino acid metabolism and cell growth, the aim of the present study was to identify these transporters in bovine mammary glands and to analyze the potential functions of these transporters in mammary epithelial cells. Abundance of PepT1 and PepT2 mRNA was successfully measured in both mammary glands and cultured mammary epithelial cells. In addition, the two proteins were examined using immunohistochemistry, immunocytochemistry, and Western blots. The response of mammary epithelial cells to tripeptide and lactogenic hormone treatment was assayed. The PepT mRNA abundance of cultured epithelial cells and secreted protein in the culture medium were increased after tri-peptide substitution and addition of hormones such as insulin, hydrocortisone, and prolactin. The response of mammary epithelial cells to tripeptide and hormone treatments suggests that PepT affects the mammary gland function and increases bovine milk production.
Akers R.M. (2006): Major Advances Associated with Hormone and Growth Factor Regulation of Mammary Growth and Lactation in Dairy Cows. Journal of Dairy Science, 89, 1222-1234
https://doi.org/10.3168/jds.S0022-0302(06)72191-9
Alcorn J. (): Transporter Gene Expression in Lactating and Nonlactating Human Mammary Epithelial Cells Using Real-Time Reverse Transcription-Polymerase Chain Reaction. Journal of Pharmacology and Experimental Therapeutics, 303, 487-496
https://doi.org/10.1124/jpet.102.038315
Avissar N., Ziegler T., Wang H., Gu L., Miller J., Iannoli P, Leibach F., Ganapathy V, Sax H. (2001): Growth factors regulation of rabbit sodium-dependent neutral amino acid transporter ATB0 and oligopeptide transporter 1 mRNAs expression after enteretomy. Journal of Parenteral and Enteral Nutrition, 25, 65-72
https://doi.org/10.1177/014860710102500265
Boll M., Herget M., Wagener M., Weber W. M., Markovich D., Biber J., Clauss W., Murer H., Daniel H. (1996): Expression cloning and functional characterization of the kidney cortex high-affinity proton-coupled peptide transporter.. Proceedings of the National Academy of Sciences, 93, 284-289
https://doi.org/10.1073/pnas.93.1.284
Bravo S. A. (2004): Epidermal growth factor decreases PEPT2 transport capacity and expression in the rat kidney proximal tubule cell line SKPT0193 cl.2. AJP: Renal Physiology, 286, 385F-393
https://doi.org/10.1152/ajprenal.00226.2003
Brennan A. J, Sharp J. A, Lefevre C. M, Nicholas K. R (2008): Uncoupling the mechanisms that facilitate cell survival in hormone-deprived bovine mammary explants. Journal of Molecular Endocrinology, 41, 103-116
https://doi.org/10.1677/JME-08-0035
Chen H., Pan Y., Wong E.A., Bloomquist J.R., Webb K.E. (2002): Molecular cloning and functional expression of a chicken intestinal peptide transporter (cPepT1) in xenopus oocytes and Chinese hamster ovary cells. The Journal of Nutrition, 132, 387–393.
Chen H, Wong E A, Webb K E (1999): Tissue distribution of a peptide transporter mRNA in sheep, dairy cows, pigs, and chickens.. Journal of Animal Science, 77, 1277-
https://doi.org/10.2527/1999.7751277x
Kottra Gabor, Daniel Hannelore (2004): The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pfl�gers Archiv European Journal of Physiology, 447, 610-618
https://doi.org/10.1007/s00424-003-1101-4
Fei You-Jun, Kanai Yoshikatsu, Nussberger Stephan, Ganapathy Vadivel, Leibach Frederick H., Romero Michael F., Singh Satish K., Boron Walter F., Hediger Matthias A. (1994): Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature, 368, 563-566
https://doi.org/10.1038/368563a0
Fei You-Jun, Sugawara Mitsura, Liu Jin-Cai, Li Hui Wu, Ganapathy Vadivel, Ganapathy Malliga E., Leibach Frederick H. (2000): cDNA structure, genomic organization, and promoter analysis of the mouse intestinal peptide transporter PEPT1. Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, 1492, 145-154
https://doi.org/10.1016/S0167-4781(00)00101-9
FEI You-Jun, FUJITA Takuya, LAPP David F., GANAPATHY Vadivel, LEIBACH Frederick H. (): Two oligopeptide transporters from Caenorhabditis elegans:molecular cloning and functional expression. Biochemical Journal, 332, 565-572
https://doi.org/10.1042/bj3320565
Groneberg David A., Döring Frank, Theis Stephan, Nickolaus Monika, Fischer Axel, Daniel Hannelore (): Peptide transport in the mammary gland: expression and distribution of PEPT2 mRNA and protein. American Journal of Physiology - Endocrinology And Metabolism, 282, E1172-E1179
https://doi.org/10.1152/ajpendo.00381.2001
Groneberg David A., Nickolaus Monika, Springer Jochen, Döring Frank, Daniel Hannelore, Fischer Axel (2001): Localization of the Peptide Transporter PEPT2 in the Lung. The American Journal of Pathology, 158, 707-714
https://doi.org/10.1016/S0002-9440(10)64013-8
Hosseinzadeh Zohreh, Dong Luo, Bhavsar Shefalee K., Warsi Jamshed, Almilaji Ahmad, Lang Florian (2013): Upregulation of Peptide Transporters PEPT1 and PEPT2 by Janus Kinase JAK2. Cellular Physiology and Biochemistry, 31, 673-682
https://doi.org/10.1159/000350086
Inui K.-i. (): Physiological and pharmacological implications of peptide transporters, PEPT1 and PEPT2. Nephrology Dialysis Transplantation, 15, 11-13
https://doi.org/10.1093/ndt/15.suppl_6.11
Kabotyanski E. B., Rijnkels M., Freeman-Zadrowski C., Buser A. C., Edwards D. P., Rosen J. M. (): Lactogenic Hormonal Induction of Long Distance Interactions between -Casein Gene Regulatory Elements. Journal of Biological Chemistry, 284, 22815-22824
https://doi.org/10.1074/jbc.M109.032490
Kottra G. (): PEPT1 as a Paradigm for Membrane Carriers That Mediate Electrogenic Bidirectional Transport of Anionic, Cationic, and Neutral Substrates. Journal of Biological Chemistry, 277, 32683-32691
https://doi.org/10.1074/jbc.M204192200
Lee Yi-Ju, Hsu Tsai-Ching, Du Jyun-Yi, Valentijn Anthony J., Wu Tung-Yi, Cheng Cheng-Fu, Yang Zhihong, Streuli Charles H. (2009): Extracellular matrix controls insulin signaling in mammary epithelial cells through the RhoA/Rok pathway. Journal of Cellular Physiology, 220, 476-484
https://doi.org/10.1002/jcp.21793
Liang Rong, Fei You-Jun, Prasad Puttur D., Ramamoorthy Sammanda, Han Hong, Yang-Feng Teresa L., Hediger Matthias A., Ganapathy Vadivel, Leibach Frederick H. (1995): Human Intestinal H
+ /Peptide Cotransporter. Journal of Biological Chemistry, 270, 6456-6463
https://doi.org/10.1074/jbc.270.12.6456
Lu Hong, Klaassen Curtis (2006): Tissue distribution and thyroid hormone regulation of Pept1 and Pept2 mRNA in rodents. Peptides, 27, 850-857
https://doi.org/10.1016/j.peptides.2005.08.012
Lyons J. A., Parker J. L., Solcan N., Brinth A., Li D., Shah S. T., Caffrey M., Newstead S. (): Structural basis for polyspecificity in the POT family of proton-coupled oligopeptide transporters. EMBO reports, 15, 886-893
https://doi.org/10.15252/embr.201338403
Meissner B., Boll M., Daniel H., Baumeister R. (): Deletion of the Intestinal Peptide Transporter Affects Insulin and TOR Signaling in Caenorhabditis elegans. Journal of Biological Chemistry, 279, 36739-36745
https://doi.org/10.1074/jbc.M403415200
Oakes Samantha R., Rogers Renee L., Naylor Matthew J., Ormandy Christopher J. (2008): Prolactin Regulation of Mammary Gland Development. Journal of Mammary Gland Biology and Neoplasia, 13, 13-28
https://doi.org/10.1007/s10911-008-9069-5
Ronnestad I., Gavaia P.J., Viegas C.S.B., Verri T., Romano A., Nilsen T.O., Jordal A.E.O., Kamisaka Y., Cancela M.L. (2007): Oligopeptide transporter PepT1 in Atlantic cod (Gadus morhua L.): cloning, tissue expression and comparative aspects. Journal of Experimental Biology, 210, 3883–3896.
Rubio-Aliaga Isabel, Boll Michael, Daniel Hannelore (2000): Cloning and Characterization of the Gene Encoding the Mouse Peptide Transporter PEPT2. Biochemical and Biophysical Research Communications, 276, 734-741
https://doi.org/10.1006/bbrc.2000.3546
Sala-Rabanal M., Loo D. D. F., Hirayama B. A., Wright E. M. (2008): Molecular mechanism of dipeptide and drug transport by the human renal H+/oligopeptide cotransporter hPEPT2. AJP: Renal Physiology, 294, F1422-F1432
https://doi.org/10.1152/ajprenal.00030.2008
Shen Hong, Smith David E., Keep Richard F., Brosius Frank C. (2004): Immunolocalization of the Proton-Coupled Oligopeptide Transporter PEPT2 in Developing Rat Brain. Molecular Pharmaceutics, 1, 248-256
https://doi.org/10.1021/mp049944b
Shen H., Smith D.E., Yang T., Huang Y.G., Schnermann J.B., Brosius F.C. (1999): Localization of PEPT1 and PEPT2 proton-coupled oligopeptide transporter mRNA and protein in rat kidney. American Journal of Physiology – Renal Physiology, 276, F658–F665.
Shimakura J. (2005): Characterization of the human peptide transporter PEPT1 promoter: Sp1 functions as a basal transcriptional regulator of human PEPT1. AJP: Gastrointestinal and Liver Physiology, 289, G471-G477
https://doi.org/10.1152/ajpgi.00025.2005
Shimakura Jin, Terada Tomohiro, Shimada Yutaka, Katsura Toshiya, Inui Ken-ichi (2006): The transcription factor Cdx2 regulates the intestine-specific expression of human peptide transporter 1 through functional interaction with Sp1. Biochemical Pharmacology, 71, 1581-1588
https://doi.org/10.1016/j.bcp.2006.03.001
Shiraga Toshiyuki, Miyamoto Ken-Ichi, Tanaka Hiroko, Yamamoto Hironori, Taketani Yutaka, Morita Kyoko, Tamai Ikumi, Tsuji Akira, Takeda Eiji (1999): Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/peptide transporter PepT1. Gastroenterology, 116, 354-362
https://doi.org/10.1016/S0016-5085(99)70132-0
Spanier Britta (2014): Transcriptional and functional regulation of the intestinal peptide transporter PEPT1. The Journal of Physiology, 592, 871-879
https://doi.org/10.1113/jphysiol.2013.258889
Warsi Jamshed, Hosseinzadeh Zohreh, Dong Luo, Pakladok Tatsiana, Umbach Anja T., Bhavsar Shefalee K., Shumilina Ekaterina, Lang Florian (2013): Effect of Janus Kinase 3 on the Peptide Transporters PEPT1 and PEPT2. The Journal of Membrane Biology, 246, 885-892
https://doi.org/10.1007/s00232-013-9582-3
Zhou M. M., Wu Y. M., Liu H. Y., Zhao K., Liu J. X. (2011): Effects of tripeptides and lactogenic hormones on oligopeptide transporter 2 in bovine mammary gland. Journal of Animal Physiology and Animal Nutrition, 95, 781-789
https://doi.org/10.1111/j.1439-0396.2010.01110.x
Akers R.M. (2006): Major Advances Associated with Hormone and Growth Factor Regulation of Mammary Growth and Lactation in Dairy Cows. Journal of Dairy Science, 89, 1222-1234
https://doi.org/10.3168/jds.S0022-0302(06)72191-9
Alcorn J. (): Transporter Gene Expression in Lactating and Nonlactating Human Mammary Epithelial Cells Using Real-Time Reverse Transcription-Polymerase Chain Reaction. Journal of Pharmacology and Experimental Therapeutics, 303, 487-496
https://doi.org/10.1124/jpet.102.038315
Avissar N., Ziegler T., Wang H., Gu L., Miller J., Iannoli P, Leibach F., Ganapathy V, Sax H. (2001): Growth factors regulation of rabbit sodium-dependent neutral amino acid transporter ATB0 and oligopeptide transporter 1 mRNAs expression after enteretomy. Journal of Parenteral and Enteral Nutrition, 25, 65-72
https://doi.org/10.1177/014860710102500265
Boll M., Herget M., Wagener M., Weber W. M., Markovich D., Biber J., Clauss W., Murer H., Daniel H. (1996): Expression cloning and functional characterization of the kidney cortex high-affinity proton-coupled peptide transporter.. Proceedings of the National Academy of Sciences, 93, 284-289
https://doi.org/10.1073/pnas.93.1.284
Bravo S. A. (2004): Epidermal growth factor decreases PEPT2 transport capacity and expression in the rat kidney proximal tubule cell line SKPT0193 cl.2. AJP: Renal Physiology, 286, 385F-393
https://doi.org/10.1152/ajprenal.00226.2003
Brennan A. J, Sharp J. A, Lefevre C. M, Nicholas K. R (2008): Uncoupling the mechanisms that facilitate cell survival in hormone-deprived bovine mammary explants. Journal of Molecular Endocrinology, 41, 103-116
https://doi.org/10.1677/JME-08-0035
Chen H., Pan Y., Wong E.A., Bloomquist J.R., Webb K.E. (2002): Molecular cloning and functional expression of a chicken intestinal peptide transporter (cPepT1) in xenopus oocytes and Chinese hamster ovary cells. The Journal of Nutrition, 132, 387–393.
Chen H, Wong E A, Webb K E (1999): Tissue distribution of a peptide transporter mRNA in sheep, dairy cows, pigs, and chickens.. Journal of Animal Science, 77, 1277-
https://doi.org/10.2527/1999.7751277x
Kottra Gabor, Daniel Hannelore (2004): The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pfl�gers Archiv European Journal of Physiology, 447, 610-618
https://doi.org/10.1007/s00424-003-1101-4
Fei You-Jun, Kanai Yoshikatsu, Nussberger Stephan, Ganapathy Vadivel, Leibach Frederick H., Romero Michael F., Singh Satish K., Boron Walter F., Hediger Matthias A. (1994): Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature, 368, 563-566
https://doi.org/10.1038/368563a0
Fei You-Jun, Sugawara Mitsura, Liu Jin-Cai, Li Hui Wu, Ganapathy Vadivel, Ganapathy Malliga E., Leibach Frederick H. (2000): cDNA structure, genomic organization, and promoter analysis of the mouse intestinal peptide transporter PEPT1. Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, 1492, 145-154
https://doi.org/10.1016/S0167-4781(00)00101-9
FEI You-Jun, FUJITA Takuya, LAPP David F., GANAPATHY Vadivel, LEIBACH Frederick H. (): Two oligopeptide transporters from Caenorhabditis elegans:molecular cloning and functional expression. Biochemical Journal, 332, 565-572
https://doi.org/10.1042/bj3320565
Groneberg David A., Döring Frank, Theis Stephan, Nickolaus Monika, Fischer Axel, Daniel Hannelore (): Peptide transport in the mammary gland: expression and distribution of PEPT2 mRNA and protein. American Journal of Physiology - Endocrinology And Metabolism, 282, E1172-E1179
https://doi.org/10.1152/ajpendo.00381.2001
Groneberg David A., Nickolaus Monika, Springer Jochen, Döring Frank, Daniel Hannelore, Fischer Axel (2001): Localization of the Peptide Transporter PEPT2 in the Lung. The American Journal of Pathology, 158, 707-714
https://doi.org/10.1016/S0002-9440(10)64013-8
Hosseinzadeh Zohreh, Dong Luo, Bhavsar Shefalee K., Warsi Jamshed, Almilaji Ahmad, Lang Florian (2013): Upregulation of Peptide Transporters PEPT1 and PEPT2 by Janus Kinase JAK2. Cellular Physiology and Biochemistry, 31, 673-682
https://doi.org/10.1159/000350086
Inui K.-i. (): Physiological and pharmacological implications of peptide transporters, PEPT1 and PEPT2. Nephrology Dialysis Transplantation, 15, 11-13
https://doi.org/10.1093/ndt/15.suppl_6.11
Kabotyanski E. B., Rijnkels M., Freeman-Zadrowski C., Buser A. C., Edwards D. P., Rosen J. M. (): Lactogenic Hormonal Induction of Long Distance Interactions between -Casein Gene Regulatory Elements. Journal of Biological Chemistry, 284, 22815-22824
https://doi.org/10.1074/jbc.M109.032490
Kottra G. (): PEPT1 as a Paradigm for Membrane Carriers That Mediate Electrogenic Bidirectional Transport of Anionic, Cationic, and Neutral Substrates. Journal of Biological Chemistry, 277, 32683-32691
https://doi.org/10.1074/jbc.M204192200
Lee Yi-Ju, Hsu Tsai-Ching, Du Jyun-Yi, Valentijn Anthony J., Wu Tung-Yi, Cheng Cheng-Fu, Yang Zhihong, Streuli Charles H. (2009): Extracellular matrix controls insulin signaling in mammary epithelial cells through the RhoA/Rok pathway. Journal of Cellular Physiology, 220, 476-484
https://doi.org/10.1002/jcp.21793
Liang Rong, Fei You-Jun, Prasad Puttur D., Ramamoorthy Sammanda, Han Hong, Yang-Feng Teresa L., Hediger Matthias A., Ganapathy Vadivel, Leibach Frederick H. (1995): Human Intestinal H
+ /Peptide Cotransporter. Journal of Biological Chemistry, 270, 6456-6463
https://doi.org/10.1074/jbc.270.12.6456
Lu Hong, Klaassen Curtis (2006): Tissue distribution and thyroid hormone regulation of Pept1 and Pept2 mRNA in rodents. Peptides, 27, 850-857
https://doi.org/10.1016/j.peptides.2005.08.012
Lyons J. A., Parker J. L., Solcan N., Brinth A., Li D., Shah S. T., Caffrey M., Newstead S. (): Structural basis for polyspecificity in the POT family of proton-coupled oligopeptide transporters. EMBO reports, 15, 886-893
https://doi.org/10.15252/embr.201338403
Meissner B., Boll M., Daniel H., Baumeister R. (): Deletion of the Intestinal Peptide Transporter Affects Insulin and TOR Signaling in Caenorhabditis elegans. Journal of Biological Chemistry, 279, 36739-36745
https://doi.org/10.1074/jbc.M403415200
Oakes Samantha R., Rogers Renee L., Naylor Matthew J., Ormandy Christopher J. (2008): Prolactin Regulation of Mammary Gland Development. Journal of Mammary Gland Biology and Neoplasia, 13, 13-28
https://doi.org/10.1007/s10911-008-9069-5
Ronnestad I., Gavaia P.J., Viegas C.S.B., Verri T., Romano A., Nilsen T.O., Jordal A.E.O., Kamisaka Y., Cancela M.L. (2007): Oligopeptide transporter PepT1 in Atlantic cod (Gadus morhua L.): cloning, tissue expression and comparative aspects. Journal of Experimental Biology, 210, 3883–3896.
Rubio-Aliaga Isabel, Boll Michael, Daniel Hannelore (2000): Cloning and Characterization of the Gene Encoding the Mouse Peptide Transporter PEPT2. Biochemical and Biophysical Research Communications, 276, 734-741
https://doi.org/10.1006/bbrc.2000.3546
Sala-Rabanal M., Loo D. D. F., Hirayama B. A., Wright E. M. (2008): Molecular mechanism of dipeptide and drug transport by the human renal H+/oligopeptide cotransporter hPEPT2. AJP: Renal Physiology, 294, F1422-F1432
https://doi.org/10.1152/ajprenal.00030.2008
Shen Hong, Smith David E., Keep Richard F., Brosius Frank C. (2004): Immunolocalization of the Proton-Coupled Oligopeptide Transporter PEPT2 in Developing Rat Brain. Molecular Pharmaceutics, 1, 248-256
https://doi.org/10.1021/mp049944b
Shen H., Smith D.E., Yang T., Huang Y.G., Schnermann J.B., Brosius F.C. (1999): Localization of PEPT1 and PEPT2 proton-coupled oligopeptide transporter mRNA and protein in rat kidney. American Journal of Physiology – Renal Physiology, 276, F658–F665.
Shimakura J. (2005): Characterization of the human peptide transporter PEPT1 promoter: Sp1 functions as a basal transcriptional regulator of human PEPT1. AJP: Gastrointestinal and Liver Physiology, 289, G471-G477
https://doi.org/10.1152/ajpgi.00025.2005
Shimakura Jin, Terada Tomohiro, Shimada Yutaka, Katsura Toshiya, Inui Ken-ichi (2006): The transcription factor Cdx2 regulates the intestine-specific expression of human peptide transporter 1 through functional interaction with Sp1. Biochemical Pharmacology, 71, 1581-1588
https://doi.org/10.1016/j.bcp.2006.03.001
Shiraga Toshiyuki, Miyamoto Ken-Ichi, Tanaka Hiroko, Yamamoto Hironori, Taketani Yutaka, Morita Kyoko, Tamai Ikumi, Tsuji Akira, Takeda Eiji (1999): Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/peptide transporter PepT1. Gastroenterology, 116, 354-362
https://doi.org/10.1016/S0016-5085(99)70132-0
Spanier Britta (2014): Transcriptional and functional regulation of the intestinal peptide transporter PEPT1. The Journal of Physiology, 592, 871-879
https://doi.org/10.1113/jphysiol.2013.258889
Warsi Jamshed, Hosseinzadeh Zohreh, Dong Luo, Pakladok Tatsiana, Umbach Anja T., Bhavsar Shefalee K., Shumilina Ekaterina, Lang Florian (2013): Effect of Janus Kinase 3 on the Peptide Transporters PEPT1 and PEPT2. The Journal of Membrane Biology, 246, 885-892
https://doi.org/10.1007/s00232-013-9582-3
Zhou M. M., Wu Y. M., Liu H. Y., Zhao K., Liu J. X. (2011): Effects of tripeptides and lactogenic hormones on oligopeptide transporter 2 in bovine mammary gland. Journal of Animal Physiology and Animal Nutrition, 95, 781-789
https://doi.org/10.1111/j.1439-0396.2010.01110.x