Cell Cycle Regulation via p53 Phosphorylation by a 5′-AMP Activated Protein Kinase Activator, 5-Aminoimidazole- 4-Carboxamide-1-β- -Ribofuranoside, in a Human Hepatocellular Carcinoma Cell Line

Imamura, Kazuhiro; Ogura, Tsutomu; Kishimoto, Atsuhiro; Kaminishi, Michio; Esumi, Hiroyasu

doi:10.1006/bbrc.2001.5627

Cited by 327 publications

(281 citation statements)

References 22 publications

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“…40 This AMPK-regulated glucose-sensitive p53-dependent cell cycle checkpoint may act as a buffer to prevent cells from entering into an energy-deficit-state that can trigger cell death. [41][42][43] Thus, p53-deficient cells fail to arrest in response to AMPK activation and continue to proliferate under low-glucose conditions. Similarly, Drosophila melanogaster cells bearing mutations in their single AMPKα gene proliferate to give rise to tumor-like overgrowths under low-energy conditions.…”

Section: Resultsmentioning

confidence: 99%

“…Since AMPK is a kinase, it could be assumed that is phosphorylates a yet-to-be-identified substrate(s) at the centrosome that may affect centrosomalemanating signaling. In this regard, it is tempting to speculate that the interplay between AMPK and p53 in response to bioenergetic stresses (i.e., under conditions of glucose deprivation, AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell cycle arrest) [39][40][41][42] may take place at the centrosomes because p53 centrosomal localization during mitosis and postmitotic checkpoint similarly require serine 15 phosphorylation. 47 Alternatively, it is possible that P-AMPKα Thr172 migrates to the centrosome in order to receive certain signals from the centrosomal complex.…”

Section: Discussionmentioning

confidence: 99%

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The active form of the metabolic sensor AMP-activated protein kinase α (AMPKα) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis

Vázquez-Martín

Oliveras‐Ferraros²,

Menéndez³

2009

Cell Cycle

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(2009) The active form of the metabolic sensor AMP-activated protein kinase α (AMPKα) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis, Cell Cycle, 8:15, 2385Cycle, 8:15, -2398 The metabolic rheostat AMP-activated protein kinase (AMPK) is unexpectedly required for proper cell division and faithful chromosomal segregation during mitosis. Although it is conceptually attractive to assume that AMPK-interpreted microenvironmental bioenergetics may strictly engage cell's energy status, cell grow, and cell division to avoid that energy stresses trigger cell death, the ultimate framework of AMPK activity towards chromosomal and cytoskeletal mitotic regulation is a question that remains unanswered. We herein reveal that the active form of the α-catalytic AMPK subunit (P-AMPKα Thr172 )-but not its total form (AMPKα)-transiently associates with several mitotic structures including centrosomes, spindle poles, the central spindle midzone and the midbody throughout all of the mitotic stages and cytokinesis in human cancer-derived epithelial cells. At prophase, P-AMPKα Thr172 associates with the two asters of microtubules that begin to nucleate from mature centrosomes. The overlapping localization of P-AMPKα Thr172 with the mitotic centrosomal Aurora-A kinase is also apparent on the microtubules near the spindle poles in metaphase and in early anaphase. This Aurora A-like centrosomal localization of P-AMPKα Thr172 cannot be detected following chromatid separation following anaphase-telophase transition. Rather, toward the end of anaphase and in telophase P-AMPKα Thr172 reactivity exhibited a similar but not identical localization to that occupied by the bona fide chromosomal passenger proteins INCENCP and Aurora-B. This localization of P-AMPKα Thr172 at the central spindle and midbody persisted during the furrowing process and, at the completion of telophase, staining of P-AMPKα Thr172 as doublet was apparent on either side of the midbody within the intercellular cytokinetic bridge. An identical mitotic geography of P-AMPKα Thr172 was observed in cancer cells lacking the AMPK kinase LKB1, in non-cancerous human epithelial cells, and in mouse fibroblasts. The active form of AMPKα bound to the mitotic apparatus may physically tether the bioenergetic state of a cell to the four-dimensional regulation of the chromosomal and cytoskeletal mitotic events, thus suggesting a putative cytokinetic suppressor function. In this newly discovered scenario, we suggest a primordial mitotic role for the α catalytic AMPK subunit in the eukaryotic evolutionary process as it may ensure, at the cell level, an exquisite coordination between sensing of energy resources and the fundamental biological process of genome division.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The active form of the metabolic sensor AMP-activated protein kinase α (AMPKα) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis

Vázquez-Martín

Oliveras‐Ferraros²,

Menéndez³

2009

Cell Cycle

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“…Thus, these data raise the possibility that AMPKa affects transcription by modifying histone phosphorylation, although it remains to be determined which residues and histones are targeted by AMPKa. It was recently reported that AMPK activation induces the phosphorylation of p53 on serine 15 (in human; serine 18 in mouse) resulting in cell-cycle arrest (Imamura et al, 2001;Jones et al, 2005). In addition, AMPK-induced p53 activation promotes cell survival in response to glucose starvation, which is distinct from p53 activation in response to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Kinase activity-independent suppression of p73α by AMP-activated kinase α (AMPKα)

et al. 2008

Oncogene

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Although p73a induces many of the same cellular events as p53, it is structurally distinct from p53 in that it possesses a unique COOH-terminal domain. To dissect the function of this domain, we performed yeast twohybrid screening of a HeLa cDNA library using residues 552-636 of p73a as bait. Among the clones that showed a specific interaction with p73a was AMP-activated protein kinase a (AMPKa). Additional yeast two-hybrid assays indicated that the bc-binding domain of AMPKa is critical for the interaction with p73a. The interaction was further confirmed in vitro by glutathione S-transferase pull-down, and in vivo by immunoprecipitation and immunofluorescence microscopy. Transient coexpression of AMPKa resulted in downregulation of the effect of p73a, but not of p53, on various p53-responsive promoters. Chromatin immunoprecipitation indicated p73a-dependent recruitment of AMPKa to the p21WAF1 promoter. Treatment with 5-aminoimidazole-4-carboxamide ribonucleotide, an agonist of AMPKa, and expression of dominant-negative versions of AMPKa revealed that the repression of p73a was independent of AMPKa kinase activity. In addition, cisplatin-induced growth repression was impaired when AMPKa was overexpressed. Upon the knock down of AMPKa by siRNA, the induction of p21WAF1 by p73a was significantly increased. Taken together, these data indicate that AMPKa specifically regulates p73a by a direct interaction without affecting its phosphorylation status. From these data, we speculate that AMPKa may provide a molecular clue to understand the repressive role of the C-terminus of p73a in transcription and DNA damage response.

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“…We introduced p53 into Hep3B human hepatocellular carcinoma cells, which have been reported to be p53 null (Imamura et al, 2001) and transiently expressed WT NUAK1. As NUAK1 has been reported to regulate the phosphorylation of p53 through ataxia telangiectasia mutation (ATM) (Suzuki et al, 2003b), ATM siRNA pool was co-transfected together with NUAK1, to address whether ATM was crucial in this regulation.…”

Section: Nuak1 Directly Phosphorylates P53mentioning

confidence: 99%

A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

Hou

Liu

et al. 2011

Oncogene

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It has been suggested that adenosine monophosphateactivated protein kinase (AMPK) and 12 AMPK-related kinases (ARK), including novel (nua) kinase family 1 (NUAK1), are activated by master kinase LKB1, a major tumor suppressor. Apart from evidence to suggest that NUAK1 participates in induction of tumor survival, invasion and p53-independent cellular senescence, its detailed biological functions remain unclear. Here we showed that in the presence of wild-type LKB1, NUAK1 directly interacts with and phosphorylates p53 in vitro and in vivo. The phosphorylation of p53 induced by LKB1 required the kinase activity of NUAK1 and phosphorylation of NUAK1 at Thr211 by LKB1 was essential for its kinase activity, which leads to the conclusion that LKB1 activates NUAK1 and regulates phosphorylation of p53 through the NUAK1 kinase, at least partially. LKB1/ NUAK1 activation leads to cell cycle arrest at the G 1 /S border by inducing expression of p21/WAF1. Under the regulation of LKB1, NUAK1 interacts with p53 in the nucleus and binds to the p53-responsive element of p21/WAF1 promoter. These findings have highlighted a novel role for NUAK1 in LKB1-related signaling pathways; NUAK1 can regulate cell proliferation and exert tumor suppression through direct interaction with p53.

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Cell Cycle Regulation via p53 Phosphorylation by a 5′-AMP Activated Protein Kinase Activator, 5-Aminoimidazole- 4-Carboxamide-1-β- -Ribofuranoside, in a Human Hepatocellular Carcinoma Cell Line

Cited by 327 publications

References 22 publications

The active form of the metabolic sensor AMP-activated protein kinase α (AMPKα) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis

The active form of the metabolic sensor AMP-activated protein kinase α (AMPKα) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis

Kinase activity-independent suppression of p73α by AMP-activated kinase α (AMPKα)

A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

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