Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase

doi:10.1016/0092-8674(94)90582-7

Cell

Volume 78, Issue 1, 15 July 1994, Pages 161-172

https://doi.org/10.1016/0092-8674(94)90582-7 Get rights and content

Abstract

Cyclin A-kinase, an enzyme required for coordinating S phase progression, forms stable in vivo complexes with E2F-1, a growth-promoting transcription factor, which binds to the retinoblastoma gene product and is involved in the timely activation of genes whose products contribute to G1 exit and S phase traversal. Complex formation results in a negative biochemical effect of cyclin A-kinase: the shut-off of E2F-1-dependent DNA binding function in S/G2. Thus, specific and timely cell cycle-dependent interactions of E2F-1 with proteins that inhibit its function (i.e., RB during G1 and cyclin A-kinase during S/G2) may contribute to the periodicity of expression of certain E2F-1-responsive genes at the G1/S transition.

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Citation Excerpt :
However, regulation of E2F1 by Skp2 and cyclin A is not fully understood (Marti et al., 1999). E2F1 DNA binding and transcriptional activity are regulated by cyclin A-cdk2 (Krek et al., 1994, 1995) and direct interactions between cyclin A and E2F1 have been reported (Krek et al., 1994, 1995; Dynlacht et al., 1994; Xu et al., 1994), but Skp2 did not compete with E2F1 binding to cyclin A (Lu et al., 2014). In this report we provide evidence that MAGE-A11 is engaged in direct interactions with Skp2 and cyclin A that regulate the target-specific activity of Skp2.
Melanoma antigen-A11 (MAGE-A11) is a proto-oncogene involved in androgen receptor signaling and androgen-dependent cell growth. In this report we provide evidence that MAGE-A11 interacts with Skp2 (S phase kinase-associated protein), the substrate recognition protein of the Skp1-Cullin1-F-box E3 ubiquitin ligase, and with Skp2 binding protein, cyclin A. A similar cyclin A binding motif in MAGE-A11 and Skp2 was consistent with a competitive relationship between MAGE-A11 and Skp2 in binding cyclin A. Skp2 inhibited MAGE-A11 interaction with cyclin A. Differential effects of MAGE-A11 on Skp2-mediated protein degradation were also revealed. MAGE-A11 increased Skp2-mediated degradation of cyclin A and retinoblastoma-related protein p130. In contrast, MAGE-A11 decreased Skp2-mediated degradation of E2F1 and Skp2 self-ubiquitination. Stabilization of E2F1 by MAGE-A11 was associated with sequestration and inactivation of Skp2 through the formation of an E2F1-MAGE-A11-Skp2 complex. We conclude that direct interactions of MAGE-A11 with Skp2 and cyclin A regulate the substrate-specificity of Skp2-mediated protein degradation.
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Cell

Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase

Abstract

Cell

Cell

J. Biol. Chem.

Cell

Cell

Cell

Cell

Cell

Cell

Trends Biochem. Sci.

Curr. Opin. Cell Biol.

Cell

Cell

Biochem. Biophys. Res. Commun.

Functional synergy between DP-1 and E2F-1 in the cell cycle regulating transcription factor DRTF1/E2F

EMBO J.

Independent binding of the retinoblastoma protein and p107 to the transcription factor E2F

Nature

Cell cycle-specific association of E2F with the p130 E1A-binding protein

Genes Dev.

Activation of human cyclin-dependent kinases in vitro

Mol. Biol. Cell

CDK2 encodes a 33-kDa cyclin A-associated protein kinase and is expressed before CDC2 in the cell cycle

Interaction of p107 with cyclin A independent of complex formation with viral oncoproteins

Science

Interaction between human cyclin A and adenovirus E1A-associated p107 protein

Science

E2F-1 mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product