Constitutive activation of a variant of the env-mpl oncogene product by disulfide-linked homodimerization.
The myeloproliferative leukemia retrovirus (MPLV) has the v-mpl cellular sequences transduced in frame with the deleted and rearranged Friend murine leukemia virus env gene. The resulting env-mpl fusion oncogene is responsible for an acute myeloproliferative disorder induced in mice by MPLV. v-mpl is a truncated form of the c-mpl gene which encodes the receptor for thrombopoietin. We investigated the contribution of the Env-Mpl extracellular domain in the constitutive activation of this truncated cytokine receptor and found that the rearrangement of the env sequences in the env-mpl fusion gene was not required for oncogenicity. A pathogenic variant, DEL3MPLV, was generated, which differs from MPLV by the deletions of 22 amino acids of the Env signal peptide, all of the mature Env sequences, and 18 N-terminal amino acids of the v-Mpl extracellular domain. The resulting del3-mpl oncogene product conserves in its extracellular region the first 12 amino acids of the Env signal sequence including a cysteine residue, and 25 amino acids of the v-Mpl. We show here that a mutation converting this cysteine to a glycine completely abolishes del3-mpl oncogenicity and that the del3-mpl oncogene product is constitutively activated by disulfide-linked homodimerization.
Courtois
G
G
Institut Cochin de Génétique Moléculaire, Institut National de la Santé et de la Recherche Médicale, Université Paris V, Hôpital Cochin, France.
Bénit
L
L
Mikaeloff
Y
Y
Pauchard
M
M
Charon
M
M
Varlet
P
P
Gisselbrecht
S
S
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D003673:Defective Viruses / Q000235:genetics; D004220:Disulfides / Q000737:chemistry; D005260:Female; D005622:Friend murine leukemia virus / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D015686:Gene Products, env / Q000737:chemistry / Q000235:genetics*; D014644:Genetic Variation; D009052:Leukemia Virus, Murine / Q000235:genetics* / Q000472:pathogenicity; D051379:Mice; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics*; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D017384:Sequence Deletion; D014774:Virulence / Q000235:genetics
D017931:DNA Primers; D004279:DNA, Viral; D004220:Disulfides; D015686:Gene Products, env; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; C082218:MPL protein, human