Polypeptide complex that regulates cell cycle and anergy

Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...

Reexamination Certificate

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C435S004000, C435S091520, C977S886000, C424S094500

Reexamination Certificate

active

07964369

ABSTRACT:
An active ubiquitin E3 ligase, GRAIL, is crucial in the induction of anergy in cells of the immune system, and in the regulation of cellular proliferation. GRAIL is shown to associate with, and be regulated by Otubain isoforms, including OTUBAIN-1 (DOG, the Destabilizer of GRAIL) and an alternative reading frame splice variant of OTUBAIN-1 (SOG, the Stabilizer of GRAIL). These proteins play opposing roles in the regulation of GRAIL auto-ubiquitination and consequently on its ability to induce anergy and regulate cellular proliferation. DOG serves as an adaptor protein, recruiting the DUB USP8. One major substrate for USP8 is the Ras exchange factor Ras-GRF1, and this protein can be found in a complex with USP8 and GRAIL, which complex is ubiquitinated by GRAIL.

REFERENCES:
Anandasabapathy; et al., “GRAIL: An E3 Ubiquitin Ligase that Inhibits Cytokine Gene Transcription is Expressed in Anergic CD4+T Cells”, Immunity, Apr. 2003, 18:535-547.
Balakirev; et al., “Otubains: a new family of cysteine proteases in the ubiquitin pathway”, EMBO Reports, Apr. 2003, 4(5):517-522.
Gnesutta; et al., “Cloning and Characterization of Mouse UBPy, a Deubiquitinating Enzyme That Interacts with the Ras Guanine Nucleotide Exchange Factor CDC25Mm/Ras-GRF1” J. Biol. Chem (2001), 276(42):39448-39454.
Kato; et al., “A Deubiquitinating Enzyme UBPY Interacts with the Src Homology 3 Domain of Hrs-binding Protein via a Novel Binding Motif PX(V/I)(D/N) RXXKP”J. Biol. Chem (2000), 275(48):37481-37487.
Nanao; et al., “Crystal structure of human otubain 2”, EMBO Reports, Jul. 2004, 5(8):783-788.
Naviglio; et al., “UBPY: a growth-regulated human ubiquitin isopeptidase” The EMBO Journal (1998), 17 (12):3241-3250.
Seroogy; et al., “The Gene Related to Anergy in Lymphocytes, an E3 Ubiquitin Ligase, Is Necessary for Anergy Induction in CD4 T Cells”, The Journal of Immunology (2004), 173:79-85.
Soares; et al., “Two isoforms of otubain 1 regulate T cell anergy via GRAIL”, Nature Immunology, Jan. 2004, 5 (1):45-54.

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