Tumor suppression in Drosophila is causally related to the function of the lethal(2)tumorous imaginal discs gene, a dnaJ homolog

Abstract

The Drosophila melanogaster tumor suppressor gene lethal(2)tumorous imaginal discs (l(2)tid) causes in homozygotes malignant growth of cells of the imaginal discs and the death of the mutant larvae at the time of puparium formation. We describe the molecular cloning of the l(2)tid+ gene and its temporal expression pattern in the wild-type and mutant alleles. Germ line rescue of the tumor phenotype was achieved with a 7.0 kb Hindlll-fragment derived from the polytene chromosome band 59F5. The l(2)tid+ gene spans approximately 2.5 kb of genomic DNA. The protein coding region, 1,696 bps long, is divided by an intron into two exons. The predicted Tid56 protein contains 518 amino acids and possesses a theoretical molecular weight of 56 kDa. It shows significant homology to all known DnaJ related proteins from bacteria, yeast, and man. The possible function of the Tid56 protein in tumor suppression is delineated.

A Mouse Homologue of the Drosophila Tumor Suppressor l(2)tid Gene Defines a Novel Ras GTPase-activating Protein (RasGAP)-binding Protein

“…The product of one clone, M3.2, spanned an open reading frame of 445 amino acids and exhibited a high degree of sequence identity with the protein product of the Drosophila tumorous imaginal disc l(2)tid gene, Tid56 (17), and the recently identified human TID1 gene, hTid-1 (18). We refer to this murine homologue of hTid-1 as mTid-1.…”

“…This deletion, which corresponds precisely to exon 5 of the human TID1 gene, 2 results in a loss of two of the four CXXCXGXG motifs. Although DnaJ proteins containing only two cysteine-rich repeats have yet to be identified, DnaJ homologs lacking the zinc finger motif altogether have already been characterized and shown to exhibit some chaperone activity (17,21,43). The expression pattern of mTid-1 mRNA in several mouse tissues was determined by Northern blot analysis using a mTid-1 I cDNA fragment (nucleotides 690 -1482) as a probe.…”

“…Searching for GAP-associated proteins is therefore of particular interest as it may lead to the identification of novel cellular components which may play an important role in Ras regulation and also, in furthering our understanding of the mechanisms by which oncogenic tyrosine kinases may effect transformation. Here we report the cloning and characterization of a novel GAP-binding protein, mTid-1, a DnaJ chaperone protein that represents the murine homolog of the Drosophila tumor suppressor l(2)tid gene (17) and the recently identified human Tid (TID1) gene (18).…”

“…Ydj1 has also been implicated as a positive regulator of cell cycle progression essential for efficient recognition and phosphorylation of cyclin CLN3 by cdc28, events that signal CLN3 degradation (28). Additional biochemical evidence suggests that members of the DnaJ and Hsp70 family interact with and modulate the growth-suppressive properties of several tumor suppressor proteins, including p53, Wilms' tumor suppressor (WT1), retinoblastoma (Rb) and the double-stranded RNA-activated protein kinase PKR (29 -36) The Drosophila l(2)tid gene is the first member of a DnaJ chaperone family to be classified as a tumor suppressor (17). Recessive mutations at the l(2)tid locus causes defects in differentiation and morphogenesis of larval imaginal discs leading to neoplastic growth of these cells into lethal tumors.…”

Identification of a hTid‐1 mutation which sensitizes gliomas to apoptosis

“…Drosophila Tid56 is the first member of the DnaJ co-chaperone family to be classified as tumor suppressor [20]. Recently, genetic studies in Drosophila have implicated l(2)tid as a novel component of the Hedgehog-Patched (Hh-Ptc) signaling pathway, which directs embryonic development and transcriptional regulation of genes such as wingless (wng) and Cubitus interruptus (Ci) that control cell proliferation and cell-fate specification [21].…”