Role of Adapter Function in Oncoprotein-mediated Activation of NF-κB

Jin, Dong Yan; Giordano, Vincenzo; Kibler, Karen V.; Nakano, Hiroyasu; Jeang, Kuan Teh

doi:10.1074/jbc.274.25.17402

Cited by 200 publications

(101 citation statements)

References 40 publications

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“…Expression vector for human CDH1 (pHACDH1) was derived from a previously described plasmid pHA containing SV40 promoters and enhancers (54). pHA was also used to express the three CDH1 mutants CDH1-4A, CDH-4D, and CDH1-AAA.…”

Section: Methodsmentioning

confidence: 99%

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Zhou

Ching

Chun

et al. 2003

Journal of Biological Chemistry

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The anaphase-promoting complex activated by CDC20 and CDH1 is a major ubiquitination system that controls the destruction of cell cycle regulators. Exactly how ubiquitination is regulated in time and space is incompletely understood. Here we report on the cell cycle-dependent localization of CDH1 and its regulation by phosphorylation. CDH1 localizes dynamically to the nucleus during interphase and to the centrosome during metaphase and anaphase. The nuclear accumulation of CDH1 correlates with a reduction in the steady-state amount of cyclin A, but not of cyclin E. A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus. On the other hand, abolition of the cyclin-binding ability of CDH1 has no influence on its nuclear localization. Taken together, our findings document the phosphorylation-dependent localization of CDH1 in vertebrate cells.The timely and orderly progression of eukaryotic cell division cycle is precisely controlled through ubiquitination-induced proteolysis. The anaphase-promoting complex (APC) 1 functions as a major ubiquitin ligase in the cell, and it governs anaphase onset, mitotic exit, and G 1 events (1-4). APC is a large complex of multiple subunits. It catalyzes the formation of polyubiquitin chains on cyclins and other cell cycle regulators and thereby targets them for degradation by proteosome. The components of APC are highly conserved in organisms ranging from yeast to humans. The rise and fall of APC activity is stringently regulated in a cell cycle-dependent manner. It plateaus at the transition from metaphase to anaphase, remains high throughout G 1 , and drops in S/G 2 until early mitosis (5). One important mechanism for the regulation of APC is through phosphorylation of its subunits (6 -9). In addition, CDC20 and CDH1 can act as activators and specificity factors of APC (10 -15).CDC20 and CDH1 are WD40 repeat proteins that associate transiently with and activate APC in a substrate-specific fashion. Many substrate proteins targeted by the CDC20-and CDH1-activated APC share a sequence motif known as destruction box (5, 16). Another motif termed the KEN box is recognized by CDH1-activated APC and has been found in substrates including CDC20, NEK2, HSL1, mitotic cyclins, and securin (17)(18)(19)(20). In addition, a distinct recognition domain called the A box has been shown to be required for CDH1-dependent ubiquitination and degradation of the Aurora-A kinase (21). Exactly how CDC20 and CDH1 activate APC remains to be fully understood. Existing evidence suggests that they mediate the temporal and spatial activation of APC throu...

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Section: Methodsmentioning

confidence: 99%

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Zhou

Ching

Chun

et al. 2003

Journal of Biological Chemistry

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“…IKKa, b and g form 700 kDa complex, in which IKKg functionally adapts Tax into this large complex (Jin et al, 1999;Jeang, 2001). The activated complex phosphorylates IkB, which detaches NF-kB, resulting in the activation of NF-kB.…”

Section: Transcriptional Activationmentioning

confidence: 99%

Human T-cell leukemia virus type I and adult T-cell leukemia

2003

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“…Recently, evidence suggests that the assembly of a transcriptionally competent 'nuclear' Tax-NF-kB-CBP complex likely first occurs in the cytoplasm (Azran et al, 2005). One prevailing view is that Tax binds the IKKg/ NEMO molecule in the cytoplasm to influence the activity of the IKKa/IKKb/IKKg complex (Chu et al, 1999;Harhaj and Sun, 1999;Jin et al, 1999a). Activated IKKa/ IKKb/IKKg complexes then phosphorylate IKKa/b leading to a cascade of events (reviewed elsewhere in this issue by Sun and Yamaoka) which result in nuclear migration of NF-kB (Iha et al, 2003).…”

Section: Structure-function Features Of Tax For Transcriptional Activmentioning

confidence: 99%