A HUMAN HOMOLOG OF THE DROSOPHILA TUMOR-SUPPRESSOR GENE L(2)GL MAPS TO 17P11.2-12 AND CODES FOR A CYTOSKELETAL PROTEIN THAT ASSOCIATES WITHNONMUSCLE MYOSIN-II HEAVY-CHAIN

Inactivation of the tumour suppressor gene lethal(2) giant larvae (D-l gl) of Drosophila leads to malignant transformation of the presumptive adult optic centers in the larval brain and tumours of the imaginal d iscs. These from the disorganization of a in which the D-LGL protein p articipates. Here we describe the isolation of a cDNA encoding the hum an homologue to the D-lgl gene designated as hugl. The hugl cDNA detec ts a locus spanning at least 25 kilobases (kb) in human chromosome ban d 17p11.2-12, which is centromeric to the p53 gene and recognizes a 4. 5 kb RNA transcript. The hugl gene is expressed in brain, kidney and m uscle but is barely seen in heart and placenta. Sequence analysis of t he hugl cDNA demonstrates a long open reading frame, which has the pot ential to encode a protein of 1057 amino acids with a predicted molecu lar weight of 115 kDaltons (kD). To further substantiate and identify the HUGL protein, we have prepared polyclonal rabbit antibodies agains t synthetic peptides corresponding to the amino and carboxyl termini o f the conceptual translation product of the hugl gene. The affinity-pu rified anti-HUGL antibodies recognize a single protein with an apparen t molecular weight of similar to 115 kD, Similar to the Drosophila pro tein, HUGL is part of a cytoskeletal network and, is associated with n onmuscle myosin II heavy chain and a kinase that specifically phosphor ylates HUGL at serine residues.