A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization.
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.
Feng
Ying-Hong
YH
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814.
Li
Xin
X
Reproductive Biology.
Wang
Liqin
L
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814.
Zhou
Lingying
L
Reproductive Biology.
Gorodeski
George I
GI
Reproductive Biology; Departments of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106; Departments of Oncology, Case Western Reserve University, Cleveland, Ohio 44106. Electronic address: gig@cwru.edu.
D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D004285:Dogs; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis*; D058486:Receptors, Purinergic P2X7; D012689:Sequence Homology, Nucleic Acid; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*
C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7