MOLECULAR BASIS OF CELL AND DEVELOPMENTAL BIOLOGY
Characterization of MyD118, Gadd45, and Proliferating Cell Nuclear Antigen (PCNA) Interacting Domains: PCNA IMPEDES MyD118 AND Gadd45-MEDIATED NEGATIVE GROWTH CONTROL*

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MyD118 and Gadd45 are related genes encoding for proteins that play important roles in negative growth control, including growth suppression and apoptosis. MyD118 and Gadd45 are related proteins that previously were shown to interact with proliferating cell nuclear antigen (PCNA), implicated in DNA replication, DNA repair, and cell cycle progression. To establish the role of MyD118 and Gadd45 interactions with PCNA, in this work we sought to identify the interacting domains and analyze the significance of this interaction in negative growth control. Using complementaryin vivo and in vitro interaction assays the N-terminal (1–46) and middle (100–127) regions of PCNA were identified as harboring MyD118- and Gadd45 interacting domains, whereas PCNA interacting domains within MyD118 and Gadd45 were localized to the C termini of these proteins (amino acids 114–156 and 137–165, respectively). These findings provide first evidence that similar domains within MyD118 and Gadd45 mediate interactions with PCNA. Importantly, ectopic expression of MyD118 or Gadd45 N-terminal peptides, lacking the PCNA interacting domain, was found to suppress colony formation or induce apoptosis more efficiently than the full-length proteins. These findings suggest that interaction of MyD118 or Gadd45 with PCNA, in essence, serves to impede negative growth control.

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This research was supported by National Institutes of Health Grant 1RO1CA43618 (to D. A. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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To whom correspondence may be addressed: Fels Inst. for Cancer Research and Molecular Biology and the Dept. of Biochemistry, Temple University School of Medicine, 3307 N. Broad St., Philadelphia, Pennsylvania 19140. Tel.: 215-707-6903/2; Fax: 215-707-2805; E-mail: [email protected] or [email protected].

© 2000 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.