The product of the ataxia-telangiectasia group D complementing gene, ATDC, interacts with a protein kinase C substrate and inhibitor.

Abstract

Ataxia-telangiectasia (AT) is an autosomal recessive human genetic disease characterized by immunological, neurological, and developmental defects and an increased risk of cancer. Cells from individuals with AT show sensitivity to ionizing radiation, elevated recombination, cell cycle abnormalities, and aberrant cytoskeletal organization. The molecular basis of the defect is unknown. A candidate AT gene (ATDC) was isolated on the basis of its ability to complement the ionizing radiation sensitivity of AT group D fibroblasts. WhetherATDC is mutated in any AT patients is not known. We have found that the ATDC protein physically interacts with the intermediate-filament protein vimentin, which is a protein kinase C substrate and colocalizing protein, and with an inhibitor of protein kinase C, hPKCI-1. Indirect immunofluorescence analysis of cultured cells transfected with a plasmid encoding an epitope-tagged ATDC protein localizes the protein to vimentin filaments. We suggest that the ATDC and hPKCI-1 proteins may be components of a signal transduction pathway that is induced by ionizing radiation and mediated by protein kinase C.Cultured cells from ataxia-telangiectasia (AT) patients show increased sensitivity to ionizing radiation and reduced cell cycle delay in G1, S, and G2 phases in responses to ionizing radiation (reviewed in ref.

ATDC (Ataxia Telangiectasia Group D Complementing) Promotes Radioresistance through an Interaction with the RNF8 Ubiquitin Ligase

“…We also found peptide sequences from histones (including histones H1.2, H2B, and H4), heat shock protein 70, ribosomal proteins (40S and 60S), and PARP1, as well as Prohibitin-2 and myristoylated alaninerich protein kinase C substrate (MARCK), which have putative roles in invasion and metastasis ( Fig. 1, Table 1) (8,(22)(23)(24). The most striking ATDC-interacting protein identified by this screen was RNF8 (37% peptide coverage by mass spectroscopy, Fig.…”

Hint1 is a haplo-insufficient tumor suppressor in mice

“…Since our discovery of HINT1 by its interaction with PKC in the yeast two-hybrid system (Klein et al, 1998), other investigators have obtained evidence that HINT1 can also interact with other proteins, including the protein ATDC, which is thought to be involved in DNA repair (Brzoska et al, 1995), the protein CDK7, which plays a role in the general apparatus of transcription (Korsisaari and Makela, 2000), and MITF, a specific bHLH-zip transcription factor (Razin et al, 1999). The latter studies are of particular interest since they indicated that Ap 4 A could modulate the transcriptional activity of MITF in mast cells (Razin et al, 1999).…”

Supersensitivity to Amphetamine in Protein Kinase-C Interacting Protein/HINT1 Knockout Mice

“…Studies in which X-ray crystallography and in vitro enzyme assays were used to elucidate the structure and function of PKCI/HINT1, suggested that it possesses nucleotidyl hydrolase or transferase activity (Lima et al, 1997). PKCI/HINT1 has also been shown to interact with the ataxia-telangiectasia group D protein and the mi transcription factor in the yeast two-hybrid system (Brzoska et al, 1995). PKCI/HINT1 KO mice display increased susceptibility to carcinogenicity, suggesting that PKCI/HINT1 may normally play a tumor suppressor role (Su et al, 2003).…”