Structure and origin of the acute promyelocytic leukemia myl/RARα cDNA and characterization of its retinoid-binding and transactivation properties

Pier Paolo Pandolfi, Francesco Grignani, Myriam Alcalay, Amedea Mencarelli, Andrea Biondi, Franceso LoCoco, Fausto Grignani, Pier Giuseppe Pelicci

Research output: Contribution to journalArticle

Abstract

Acute promyelocytic leukemia (APL) is characterized by the 15;17 chromosomal translocation. Cloning experiments have established that the chromosome 17 breakpoint maps to the RARα and the 15 to the myl locus. The resulting chimeric gene is transcribed as a myl/RARα fusion mRNA. By isolating both normal myl and APL myl/RARα cDNAs, we showed that the myl/RARα mRNA encodes for a putative fusion protein with a molecular weight of about 103 kDa, which is made up of 530 amino acids derived from the myl N-terminus and 402 amino acids originating from the RARα C-terminus. The protein includes the RARα DNA and retinoidbinding regions but lacks the A portion of the N-terminal region (A/B region) which is thought to contain one of the RARα transactivation domains. The myl/RARα protein acted as a retinoid-inducible transcription factor with both ligand-independent repressor and ligand-dependent activator functions in transactivation experiments of a retinoic acid-responsive gene. Myl/RARα exerted this dual function three times more effectively than RARα and had about 10-fold greater affinity for RA than RARα. Comparison of myl/RARα genomic and cDNA sequences from the same case demonstrated that both chromosome 15 and 17 breakpoints occurred within introns and the myl and RARα sequences are spliced in the same polyadenylated RNA.

Original languageEnglish
Pages (from-to)1285-1292
Number of pages8
JournalOncogene
Volume6
Issue number7
Publication statusPublished - Jul 1991

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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