A polymorphic form of steroidogenic factor-1 is associated with adrenocorticotropin resistance in y1 mouse adrenocortical tumor cell mutants.
ACTH resistance in mutant derivatives of the Y1 mouse adrenocortical tumor cell line results from a defect that affects the activity of steroidogenic factor-1 (SF1), thereby preventing the expression of the melanocortin-2 receptor. In this report, we show that the SF1 genes in ACTH-resistant mutants differ from the gene in ACTH-responsive Y1 cells by two base changes-one that changes an Ala to Ser at codon 172, and one in the third position of codon 3 that does not affect the protein sequence. Furthermore, several of the mutants contain multiple copies of this alternate SF1 gene (SF1(S172)) on acentric chromosome fragments. The SF1(S172) allele represents a polymorphism rather than a spontaneous mutation because the two SF1 alleles can be traced to the hybrid mouse strain (C57L/J x A/HeJ) from which the original adrenal tumor was derived. The SF1(A172) allele also is found in C57Bl/6J and C57Bl/10J mice, whereas the SF1(S172) allele also is found in C3H/HeJ and DBA/2J mice. The two forms of SF1 had only modest differences in activity suggesting that the SF1 polymorphism per se is not directly responsible for ACTH resistance. Our results indicate that the SF1(S172) allele is a marker of ACTH resistance in this family of adrenocortical tumor cells.
Frigeri
Claudia
C
Department of Pharmacology, University of Toronto, Ontario, Canada M5G 1L6.
Tsao
Jennivine
J
Cordova
Martha
M
Schimmer
Bernard P
BP
D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000483:Alleles; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051717:Fushi Tarazu Transcription Factors; D005784:Gene Amplification; D018398:Homeodomain Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear; D013045:Species Specificity; D054339:Steroidogenic Factor 1; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D000324:Adrenocorticotropic Hormone