Abstract
A truncated naturally occurring variant of the human receptor P2X7 was identified in cancer cervical cells. The novel protein (P2X7-j), a polypeptide of 258 amino acids, lacks the entire intracellular carboxyl terminus, the second transmembrane domain, and the distal third of the extracellular loop of the full-length P2X7 receptor. The P2X7-j was expressed in the plasma membrane; it showed diminished ligand-binding and channel function capacities and failed to form pores and mediate apoptosis in response to treatment with the P2X7 receptor agonist benzoyl-ATP. The P2X7-j interacted with the full-length P2X7 in a manner suggesting heterooligomerization and blocked the P2X7-mediated actions. Interestingly, P2X7-j immunoreactivity and mRNA expression were similar in lysates of human cancer and normal cervical tissues, but full-length P2X7 immunoreactivity and mRNA expression were higher in normal than in cancer tissues, and cancer tissues lacked 205-kDa P2X7 immunoreactivity suggesting lack of P2X7 homo(tri)-oligomerization. These results identify a novel P2X7 variant with apoptosis-inhibitory actions, and demonstrate a distinct regulatory property for a truncated variant to antagonize its full-length counterpart through hetero-oligomerization. This may represent a general paradigm for regulation of a protein function by its variant.
Highlights
A truncated naturally occurring variant of the human receptor P2X7 was identified in cancer cervical cells
Because human cervical epithelial cells secrete ATP into the extracellular milieu at concentrations that suffice to induce P2X7 pores [19], it was proposed that growth of cervical cells in vivo is controlled by autocrine-paracrine P2X7-mediated apoptosis [14, 15, 19, 20]
The present paper reports our discovery of a novel variant of the human P2X7 (P2X7-j) that lacks the entire intracellular carboxyl terminus, the second transmembrane domain, and the distal third of the extracellular loop of the P2X7
Summary
A truncated naturally occurring variant of the human receptor P2X7 was identified in cancer cervical cells. P2X7-j immunoreactivity and mRNA expression were similar in lysates of human cancer and normal cervical tissues, but fulllength P2X7 immunoreactivity and mRNA expression were higher in normal than in cancer tissues, and cancer tissues lacked 205-kDa P2X7 immunoreactivity suggesting lack of P2X7 homo(tri)-oligomerization These results identify a novel P2X7 variant with apoptosis-inhibitory actions, and demonstrate a distinct regulatory property for a truncated variant to antagonize its full-length counterpart through hetero-oligomerization. The present paper reports our discovery of a novel variant of the human P2X7 (P2X7-j) that lacks the entire intracellular carboxyl terminus, the second transmembrane domain, and the distal third of the extracellular loop of the P2X7 This variant was deficient in ligand binding, but interacted with the full-length P2X7 and blocked P2X7-mediated channel activity. Because in cancer cervical cells the P2X7-j is co-expressed with the wildtype P2X7 (present results), it is hypothesized that co-expression of the P2X7-j could lead to defective apoptosis and enhance the growth of the cancer cervical cells
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