Loss of the Forkhead Transcription Factor FoxM1 Causes Centrosome Amplification and Mitotic Catastrophe

Wonsey, Diane R.; Follettie, Maximillian T.

doi:10.1158/0008-5472.can-04-4059

Cited by 325 publications

(340 citation statements)

References 41 publications

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“…Previous studies link aberrant centrosomes to both defective mitosis (Mailand et al, 2002) and multinucleation (Wonsey and Follettie, 2005), both of which we show to occur after mutant p53 induction. The increased distance observed between centrosomes in mutant p53-expressing cells may be due …”

Section: Discussionsupporting

confidence: 69%

“…Mutant p53 expression is associated with chromosome segregation defects that can be suppressed by ANKRD11 As centrosome abnormalities have previously been linked to aberrant mitotic progression (Mailand et al, 2002;Wonsey and Follettie, 2005), we next examined the ability of mutant p53-expressing cells to undergo mitosis. The defects in centrosome duplication and segregation in the induced mutant p53 cells was associated with a 20-30% increase in the frequency of abnormal mitotic spindles (Figures 3a and b), and a significant increase in cells with lagging chromosomes ( Figure 3c) and anaphase bridges (Figure 3d), compared with un-induced cells.…”

Section: Introductionmentioning

confidence: 99%

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Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

et al. 2011

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Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 'hotspot' mutants promote a range of centrosome abnormalities, including centrosome amplification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53-p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

et al. 2011

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“…The depletion of mitochondrial function has recently been shown to induce MYC overexpression, and we also observed a substantial upregulation of MYC in cells bearing mtDNA deletions [40,[44][45][46][47]62] …”

Section: Single Mtdna Deletions Produce Inhibition Of Multiple Mitochsupporting

confidence: 73%

“…MYC, which has recently been shown to serve as a transcription factor for mitochondrial biogenesis, responds to mitochondrial functional depletion [40,[44][45][46][47].…”

Section: Mtdna Deletions Activate Snare Genes Stress Genes Myc and mentioning

confidence: 99%

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Alemi

Prigione

Wong

et al. 2007

Free Radical Biology and Medicine

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Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre Syndrome (KSS) and Chronic Progressive External Opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed 6 cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.

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“…Summarizing from previous studies, the expression of KIFs is regulated by the upstream transcription factor. For example, KIF1Bb is regulated by egl9 homolog 3 (EglN3), 19 MKLP1 is regulated by cut-like homeobox 1 (CUX1) and E2F transcription factor 1 (E2F1), 95 MKLP2 is regulated by forkhead box M1 (FoxM1), 61 and MCAK is regulated by Sp transcription factor 1 (Sp1) and E2F1. 96 The phosphorylation of KIFs reduced their binding to microtubules 97,98 and changed the localization and microtubule depolymerizing activity of KIF.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

The role of kinesin family proteins in tumorigenesis and progression

Feng

2010

Cancer

113

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The kinesin superfamily contains a conserved class of microtubule-dependent molecular motor proteins that possess an adenosine triphosphatase activity and motion characteristics. The active movement of kinesins supports several cellular functions, including mitosis, meiosis, and the transport of macromolecules. Mitosis is a process of eukaryotic cell division that involves the division of nuclei, cytoplasm, organelles, and the cell membrane into 2 daughter cells with roughly equivalent portions of these cellular components. Any errors in this process could result in cell death, abnormality (such as gene deletion, chromosome translocation, or duplication), and cancer. Because mitosis is complex and highly regulated, alteration of kinesin expression or function could lead to carcinogenesis. Moreover, because human cancer is a gene-related disease involving abnormal cell growth, targeting kinesins may create a novel strategy for the control of human cancer. Indeed, several such drugs are being tested successfully in the clinic. In this review, the authors discuss in detail the structure and function of kinesins, the correlation of kinesin expression with tumorigenesis and progression, and the development of biomarkers and cancer-targeted therapy involving the kinesin family proteins. Cancer 2010;116:5150-60.

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Loss of the Forkhead Transcription Factor FoxM1 Causes Centrosome Amplification and Mitotic Catastrophe

Cited by 325 publications

References 41 publications

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

The role of kinesin family proteins in tumorigenesis and progression

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