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Alternative splicing of human NT5E in cirrhosis and hepatocellular carcinoma produces a negative regulator of ecto-5'-nucleotidase (CD73).

Snider NT, Altshuler PJ, Wan S, Welling TH, Cavalcoli J, Omary MB - Mol. Biol. Cell (2014)

Bottom Line: The two human isoforms exhibited functional differences, such that ectopic expression of canonical CD73 (CD73L) in human HepG2 cells was associated with decreased expression of the proliferation marker Ki67, whereas CD73S expression did not have an effect on Ki67 expression.Furthermore, CD73S complexed with CD73L and promoted proteasome-dependent CD73L degradation.The findings reveal species-specific CD73 regulation, with potential significance to cancer, fibrosis, and other diseases characterized by changes in CD73 expression and function.

View Article: PubMed Central - PubMed

Affiliation: Departments of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.

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Proposed model for NT5E and CD73 regulation in the context of liver cirrhosis and HCC. Pre-mRNA splicing of NT5E under normal conditions results in expression of the nine-exon NT5E-1 transcript, which encodes canonical CD73 (CD73L). In the context of cirrhosis and HCC, there is significant up-regulation of the alternative splice variant NT5E-2, which encodes CD73S. CD73S is an ER-associated glycoprotein that does not dimerize and lacks 5′-nucleotidase activity. CD73S complexes with CD73L and promotes CD73L degradation via the proteasome. A potential function of CD73S may be to limit the antiproliferative and proapoptotic functions of CD73L-generated adenosine. The cell type(s) affected by CD73S induction within the diseased liver remain to be defined.
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Figure 7: Proposed model for NT5E and CD73 regulation in the context of liver cirrhosis and HCC. Pre-mRNA splicing of NT5E under normal conditions results in expression of the nine-exon NT5E-1 transcript, which encodes canonical CD73 (CD73L). In the context of cirrhosis and HCC, there is significant up-regulation of the alternative splice variant NT5E-2, which encodes CD73S. CD73S is an ER-associated glycoprotein that does not dimerize and lacks 5′-nucleotidase activity. CD73S complexes with CD73L and promotes CD73L degradation via the proteasome. A potential function of CD73S may be to limit the antiproliferative and proapoptotic functions of CD73L-generated adenosine. The cell type(s) affected by CD73S induction within the diseased liver remain to be defined.

Mentions: The inverse association between CD73L expression and Ki67 positivity in HepG2 cells suggests that CD73L may function to limit hepatoma cell proliferation. This may involve adenosine because of the known proapoptotic and antiproliferative functions of adenosine or adenosine A3 receptor agonists in these cells (Hermes et al., 2007; Cohen et al., 2011; Tamura et al., 2012). Given that CD73S promotes CD73L down-regulation, one potential function of CD73S in HCC may be to limit the antiproliferative and proapoptotic function of CD73L-generated adenosine (Figure 7). The effects of adenosine in cancer are complex and can result in different outcomes, depending upon which receptor is activated (Antonioli et al., 2013a). In general, activation of the adenosine receptors A1, A2A, and A2B promotes cancer cell proliferation, whereas activation of the A3 receptor blocks it (Antonioli et al., 2013a). Furthermore, activation of A3 receptor promotes apoptosis of cancer cells, and the adenosine A3 receptor agonist CF102 has antitumor effects in the liver (Cohen et al., 2011). Additional studies will be necessary to assess whether NT5E-2 mRNA and CD73S protein levels correlate with liver disease progression and the ultimate development of HCC.


Alternative splicing of human NT5E in cirrhosis and hepatocellular carcinoma produces a negative regulator of ecto-5'-nucleotidase (CD73).

Snider NT, Altshuler PJ, Wan S, Welling TH, Cavalcoli J, Omary MB - Mol. Biol. Cell (2014)

Proposed model for NT5E and CD73 regulation in the context of liver cirrhosis and HCC. Pre-mRNA splicing of NT5E under normal conditions results in expression of the nine-exon NT5E-1 transcript, which encodes canonical CD73 (CD73L). In the context of cirrhosis and HCC, there is significant up-regulation of the alternative splice variant NT5E-2, which encodes CD73S. CD73S is an ER-associated glycoprotein that does not dimerize and lacks 5′-nucleotidase activity. CD73S complexes with CD73L and promotes CD73L degradation via the proteasome. A potential function of CD73S may be to limit the antiproliferative and proapoptotic functions of CD73L-generated adenosine. The cell type(s) affected by CD73S induction within the diseased liver remain to be defined.
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Related In: Results  -  Collection

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Figure 7: Proposed model for NT5E and CD73 regulation in the context of liver cirrhosis and HCC. Pre-mRNA splicing of NT5E under normal conditions results in expression of the nine-exon NT5E-1 transcript, which encodes canonical CD73 (CD73L). In the context of cirrhosis and HCC, there is significant up-regulation of the alternative splice variant NT5E-2, which encodes CD73S. CD73S is an ER-associated glycoprotein that does not dimerize and lacks 5′-nucleotidase activity. CD73S complexes with CD73L and promotes CD73L degradation via the proteasome. A potential function of CD73S may be to limit the antiproliferative and proapoptotic functions of CD73L-generated adenosine. The cell type(s) affected by CD73S induction within the diseased liver remain to be defined.
Mentions: The inverse association between CD73L expression and Ki67 positivity in HepG2 cells suggests that CD73L may function to limit hepatoma cell proliferation. This may involve adenosine because of the known proapoptotic and antiproliferative functions of adenosine or adenosine A3 receptor agonists in these cells (Hermes et al., 2007; Cohen et al., 2011; Tamura et al., 2012). Given that CD73S promotes CD73L down-regulation, one potential function of CD73S in HCC may be to limit the antiproliferative and proapoptotic function of CD73L-generated adenosine (Figure 7). The effects of adenosine in cancer are complex and can result in different outcomes, depending upon which receptor is activated (Antonioli et al., 2013a). In general, activation of the adenosine receptors A1, A2A, and A2B promotes cancer cell proliferation, whereas activation of the A3 receptor blocks it (Antonioli et al., 2013a). Furthermore, activation of A3 receptor promotes apoptosis of cancer cells, and the adenosine A3 receptor agonist CF102 has antitumor effects in the liver (Cohen et al., 2011). Additional studies will be necessary to assess whether NT5E-2 mRNA and CD73S protein levels correlate with liver disease progression and the ultimate development of HCC.

Bottom Line: The two human isoforms exhibited functional differences, such that ectopic expression of canonical CD73 (CD73L) in human HepG2 cells was associated with decreased expression of the proliferation marker Ki67, whereas CD73S expression did not have an effect on Ki67 expression.Furthermore, CD73S complexed with CD73L and promoted proteasome-dependent CD73L degradation.The findings reveal species-specific CD73 regulation, with potential significance to cancer, fibrosis, and other diseases characterized by changes in CD73 expression and function.

View Article: PubMed Central - PubMed

Affiliation: Departments of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.

Show MeSH
Related in: MedlinePlus