ABCB5

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ATP-binding cassette sub-family B member 5 also known as P-glycoprotein ABCB5 is a plasma membrane-spanning protein that in humans is encoded by the ABCB5 gene.[1][2] ABCB5 is an ABC transporter and P-glycoprotein family member principally expressed in physiological skin and human malignant melanoma.[3][4][5]

Clinical significance

ABCB5 has been suggested to regulate skin progenitor cell fusion and mediate chemotherapeutic drug resistance in stem-like tumor cell subpopulations in human malignant melanoma. It is commonly over-expressed on circulating melanoma tumour cells.[6][7] Furthermore, the ABCB5+ melanoma- initiating cells were demonstrated to express FLT1 (VEGFR1) receptor tyrosine kinase which was functionally required for efficient xenograft tumor formation, as demonstrated by shRNA knockdown experiments.[8]

In colorectal cancer, ABCB5 was shown to act as a mediator of 5-FU patient chemoresistance, and had a further direct role in tumorigenesis shown by shRNA-mediated colorectal cancer cell-line ABCB5 knockdowns that impeded tumorigenesis in human-to-mouse xenografts.[9] In melanoma, ABCB5 contributes to multi-drug chemotherapy resistance, and tumor growth, controlling a proinflammatory signaling circuit utilizing TLR4, IL-1β, IL8 and CXCR1 signaling involving reciprocal paracrine interactions between the melanoma stem cell and tumor bulk population (in a rheostat manner termed "cancer stem cell rheostasis"). ABCB5 was shown to maintain the slow-cycling melanoma stem cells using this cytokine signaling loop, which became more differentiated upon ABCB5 interference (e.g. WFDC1 melanocyte differentiation marker increased, cancer cells were faster growing in vitro, tumors were more pigmented), or CXCR1 blockade (slow-cycling ABCB5+ cells entered the cell-cycle).[10]

In normal physiology ABCB5 is a functional marker for adult limbal stem cells of the cornea. ABCB5+ cells could regrow a human cornea on a mouse with limbal stem cell deficiency (LSCD - a blindness disease of the corneal limbus) while ABCB5- cells could not, indicating a therapeutic potential for treating some types of blindness. ABCB5 was further shown to be anti-apoptotic in these adult stem cells.[11]

References

  1. Allikmets R, Gerrard B, Hutchinson A, Dean M (October 1996). "Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database". Human Molecular Genetics. 5 (10): 1649–55. doi:10.1093/hmg/5.10.1649. PMID 8894702.
  2. Frank NY, Pendse SS, Lapchak PH, Margaryan A, Shlain D, Doeing C, Sayegh MH, Frank MH (November 2003). "Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter". The Journal of Biological Chemistry. 278 (47): 47156–65. doi:10.1074/jbc.M308700200. PMID 12960149.
  3. Chen KG, Szakács G, Annereau JP, Rouzaud F, Liang XJ, Valencia JC, Nagineni CN, Hooks JJ, Hearing VJ, Gottesman MM (April 2005). "Principal expression of two mRNA isoforms (ABCB 5alpha and ABCB 5beta ) of the ATP-binding cassette transporter gene ABCB 5 in melanoma cells and melanocytes". Pigment Cell Research. 18 (2): 102–12. doi:10.1111/j.1600-0749.2005.00214.x. PMC 3915408. PMID 15760339.
  4. Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM, Gasser M, Sayegh MH, Sadee W, Frank MH (May 2005). "ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma". Cancer Research. 65 (10): 4320–33. doi:10.1158/0008-5472.CAN-04-3327. PMID 15899824.
  5. Chen KG, Valencia JC, Gillet JP, Hearing VJ, Gottesman MM (December 2009). "Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma". Pigment Cell & Melanoma Research. 22 (6): 740–9. doi:10.1111/j.1755-148X.2009.00630.x. PMC 2766009. PMID 19725928.
  6. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH (January 2008). "Identification of cells initiating human melanomas". Nature. 451 (7176): 345–9. doi:10.1038/nature06489. PMC 3660705. PMID 18202660.
  7. Ma J, Lin JY, Alloo A, Wilson BJ, Schatton T, Zhan Q, Murphy GF, Waaga-Gasser AM, Gasser M, Stephen Hodi F, Frank NY, Frank MH (November 2010). "Isolation of tumorigenic circulating melanoma cells". Biochemical and Biophysical Research Communications. 402 (4): 711–7. doi:10.1016/j.bbrc.2010.10.091. PMC 2998991. PMID 20977885.
  8. Frank NY, Schatton T, Kim S, Zhan Q, Wilson BJ, Ma J, Saab KR, Osherov V, Widlund HR, Gasser M, Waaga-Gasser AM, Kupper TS, Murphy GF, Frank MH (February 2011). "VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth". Cancer Research. 71 (4): 1474–85. doi:10.1158/0008-5472.CAN-10-1660. PMC 3083845. PMID 21212411.
  9. Wilson BJ, Schatton T, Zhan Q, Gasser M, Ma J, Saab KR, Schanche R, Waaga-Gasser AM, Gold JS, Huang Q, Murphy GF, Frank MH, Frank NY (August 2011). "ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients". Cancer Research. 71 (15): 5307–16. doi:10.1158/0008-5472.CAN-11-0221. PMC 3395026. PMID 21652540.
  10. Wilson BJ, Saab KR, Ma J, Schatton T, Pütz P, Zhan Q, Murphy GF, Gasser M, Waaga-Gasser AM, Frank NY, Frank MH (August 2014). "ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit". Cancer Research. 74 (15): 4196–207. doi:10.1158/0008-5472.CAN-14-0582. PMC 4119553. PMID 24934811.
  11. Ksander BR, Kolovou PE, Wilson BJ, Saab KR, Guo Q, Ma J, McGuire SP, Gregory MS, Vincent WJ, Perez VL, Cruz-Guilloty F, Kao WW, Call MK, Tucker BA, Zhan Q, Murphy GF, Lathrop KL, Alt C, Mortensen LJ, Lin CP, Zieske JD, Frank MH, Frank NY (July 2014). "ABCB5 is a limbal stem cell gene required for corneal development and repair". Nature. 511 (7509): 353–7. doi:10.1038/nature13426. PMC 4246512. PMID 25030174.

Further reading

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