Mitochondrial Liaisons of p53

Galluzzi, Lorenzo; Morselli, Eugenia; Kepp, Oliver; Vitale, Ilio; Pinti, Marcello

doi:10.1089/ars.2010.3504

Cited by 71 publications

(64 citation statements)

References 259 publications

(270 reference statements)

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“…Activated TP53 exerts lethal functions via nuclear and cytoplasmic mechanisms that eventually lead to mitochondrial outer membrane permeabilization or increased signaling via death receptors followed by cell death (Kroemer et al, 2007;Galluzzi et al, 2011) In response to cisplatin, CHEK1 has also been shown to activate various branches of the mitogenactivated protein kinase (MAPK) system, including those mediated by extracellular signal-regulated kinases, c-JUN N-terminal kinases and stress-activated protein kinases (Persons et al, 2000;Wang et al, 2000;Dent and Grant, 2001;Yeh et al, 2002). The relative contribution of these signaling modules to the cytotoxic effects of cisplatin remain to be deciphered, as contrasting reports can be found in literature (Dent and Grant, 2001).…”

Section: Mode Of Actionmentioning

confidence: 99%

Molecular mechanisms of cisplatin resistance

et al. 2011

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Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNAcisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.

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Section: Mode Of Actionmentioning

confidence: 99%

Molecular mechanisms of cisplatin resistance

et al. 2011

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“…In particular, p53 influences mitochondrial functions such as apoptosis and respiration which is the most prominent source of ROS. p53 was shown to indirectly promote mitochondrial functions and inhibit glycolysis [21][22][23]. The consequence of this promotion of oxidative phosphorylation is a decrease in oxidative stress and thus prevention of DNA damage.…”

Section: Redox Modificationsmentioning

confidence: 99%

Antioxidant Role of p53 and of Its Target TP53INP1

Seillier¹,

Peuget²,

Dusetti³

et al. 2012

Antioxidant Enzyme

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“…However, in recent years the role of p53 in cytoplasm especially during autophagy, energy metabolism and mitochondrial functions (reviewed by Galluzzi et al, 2011;Green and Kroemer, 2009) have also come into sharper focus.…”

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confidence: 99%

RECQL4 is essential for the transport of p53 to mitochondria in normal human cells in the absence of exogenous stress

Kumari

Mudgal

et al. 2012

Journal of Cell Science

118

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SummaryMutations in RECQL4 helicase are associated with Rothmund-Thomson syndrome (RTS). A subset of RTS patients is predisposed to cancer and is sensitive to DNA damaging agents. The enhanced sensitivity of cells from RTS patients correlates with the accumulation of transcriptionally active nuclear p53. We found that in untreated normal human cells these two nuclear proteins, p53 and RECQL4, instead colocalize in the mitochondrial nucleoids. RECQL4 accumulates in mitochondria in all phases of the cell cycle except S phase and physically interacts with p53 only in the absence of DNA damage. p53-RECQL4 binding leads to the masking of the nuclear localization signal of p53. The N-terminal 84 amino acids of RECQL4 contain a mitochondrial localization signal, which causes the localization of RECQL4-p53 complex to the mitochondria. RECQL4-p53 interaction is disrupted after stress, allowing p53 translocation to the nucleus. In untreated normal cells RECQL4 optimizes de novo replication of mtDNA, which is consequently decreased in fibroblasts from RTS patients. Wild-type RECQL4-complemented RTS cells show relocalization of both RECQL4 and p53 to the mitochondria, loss of p53 activation, restoration of de novo mtDNA replication and resistance to different types of DNA damage. In cells expressing D84 RECQL4, which cannot translocate to mitochondria, all the above functions are compromised. The recruitment of p53 to the sites of de novo mtDNA replication is also regulated by RECQL4. Thus these findings elucidate the mechanism by which p53 is regulated by RECQL4 in unstressed normal cells and also delineates the mitochondrial functions of the helicase.

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Mitochondrial Liaisons of p53

Cited by 71 publications

References 259 publications

Molecular mechanisms of cisplatin resistance

Molecular mechanisms of cisplatin resistance

Antioxidant Role of p53 and of Its Target TP53INP1

RECQL4 is essential for the transport of p53 to mitochondria in normal human cells in the absence of exogenous stress

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