p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells

Dong, Peixin; Tada, Mitsuhiro; Hamada, Junichi; Nakamura, Akihiro; Moriuchi, Tetsuya; Sakuragi, Noriaki

doi:10.1007/s10585-007-9084-8

Cited by 48 publications

(42 citation statements)

References 36 publications

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“…Moreover, dominant-negative mutant p53 R273H promotes tumor cell invasion and migra- were uninduced or induced to knock down myosin VI for 72 h followed by mock treatment or treatment with 1 g/ml of doxorubicin for 48 h. The cell cycle profile was analyzed by DNA histogram analysis as described under "Experimental Procedures." tion (42). During cell migration, endocytosis is a critical step to recycle cell adhesion (integrin and cadherin) and signaling (such as chemokines) molecules for cell movement (8 -9, 43).…”

Section: Discussionmentioning

confidence: 99%

“…To test this, we generated multiple MCF7 cell lines in which myosin VI can be inducibly knocked down by siRNA under the control of the tetracycline-regulated promoter. Three representative cell lines (37,42,79) were chosen for further studies. We showed that upon induction, the level of myosin VI protein was significantly decreased, especially considering that myosin VI is a structural protein with a long half-life (Fig.…”

Section: Knockdown Of Myosin VI Inhibits P53 Stabilization and Subseqmentioning

confidence: 99%

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Myosin VI Is Differentially Regulated by DNA Damage in p53- and Cell Type-dependent Manners

Cho

Chen

2010

Journal of Biological Chemistry

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Myosin VI is an unconventional motor protein and functions in a variety of intracellular processes such as cell migration, vesicular trafficking, and homeostasis of the Golgi complex. Previously, we found that myosin VI is up-regulated in RKO, LS174T, and H1299 cells by DNA damage in a p53-dependent manner and mediates the pro-survival function of p53. Here, we showed that the levels of myosin VI protein were markedly inhibited in MCF7 and LNCaP cells by topoisomerase I-II inhibitors. However, the levels of myosin VI transcript were decreased only by topoisomerase I inhibitors. We also found that the levels of myosin VI protein were markedly inhibited in MCF7 cells by wild-type p53 but not tumor-derived mutant p53. Surprisingly, we found that the level of myosin VI transcript was slightly increased instead of decreased in MCF7 cells by p53, suggesting that a mechanism other than transcriptional repression is involved. Additionally, we found that on the myosin VI promoter, the level of acetylated histone H3 was markedly decreased, whereas that of p53 and acetylated histone H4 was slightly increased in MCF7 cells upon treatment with topoisomerase I-II inhibitors. Finally, we showed that overexpression of myosin VI enhances, whereas knockdown of myosin VI decreases, DNA damage-induced stabilization of p53, and consequently, knockdown of myosin VI de-sensitizes MCF7 cells to DNA damage-induced apoptosis. Taken together, as a mediator of the p53 pro-survival pathway and a marker of malignancy in some tumors, differential regulation of myosin VI in various tumor cells by topoisomerase inhibitors dictates whether knockdown of myosin VI inhibits, rather than enhances, the susceptibility of tumor cells to some therapeutic agents, which might be explored for designing a proper therapeutic strategy.Myosins are motor proteins to move cargos along actin filaments using the energy derived from ATP hydrolysis by actinactivated Mg 2ϩ -dependent ATPase activity (1-3). Myosins are categorized into 18 distinct classes according to variations of their amino acid sequence in the motor domain. The differences in motor and tail domains are linked to their specific biological functions in the cell (4 -5). Myosin VI is an unconventional actin-based motor protein and carries out a diverse set of functions such as maintenance of the Golgi complex, cargo sorting and vesicle formation, protein secretion, endocytosis, cell migration, spindle orientation, spermatogenesis, and cell-cell contacts (1, 6 -10). In addition, myosin VI was shown to enhance RNA polymerase II-dependent transcription through physical interaction with RNA polymerase II (11), suggesting that myosin VI has a critical function in the nucleus as well as in the cytoplasm and on the plasma membrane.Myosin VI was found to be overexpressed in high-grade ovarian carcinoma cells and knockdown of myosin VI led to impediment of cell spreading, migration, and dissemination (12). Myosin VI was also found to be one of the highly expressed genes in clinical prostate specimens and knock...

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Section: Discussionmentioning

confidence: 99%

Section: Knockdown Of Myosin VI Inhibits P53 Stabilization and Subseqmentioning

confidence: 99%

Myosin VI Is Differentially Regulated by DNA Damage in p53- and Cell Type-dependent Manners

Cho

Chen

2010

Journal of Biological Chemistry

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“…data). This requirement for cooperating oncogenic signals may explain why other studies did not find a positive role for mutp53 GOF in promoting migration (Dong et al 2007), or even found a negative role (Kalo et al 2007). Furthermore, in cells that retain a wtp53 allele, the promigratory effect of mutp53 might be exerted through a combination of GOF and dominant-negative activities (Dong et al 2007).…”

Section: Mutp53 and Cell Migration And Invasionmentioning

confidence: 98%

Mutant p53 Gain-of-Function in Cancer

Oren

Rotter²

2009

Cold Spring Harbor Perspectives in Biology

650

621

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“…1), and these mutant proteins have, therefore, an intact tetramerization domain. Formation of mixed tetramers of impaired activity between wild-type and mutant p53 is thought to be the molecular basis of the so-called dominantnegative effect of mutant p53 in heterozygous cells Chan et al 2004;Dong et al 2007;Junk et al 2008). The extent of the dominant -negative effect (or whether it is observed at all in vivo) depends on the specific mutant (Dearth et al 2007).…”

Section: Structural Basis Of Tetramer Formationmentioning

confidence: 99%

The Tumor Suppressor p53: From Structures to Drug Discovery

Joerger

Fersht²

2010

Cold Spring Harbor Perspectives in Biology

290

280

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Even 30 years after its discovery, the tumor suppressor protein p53 is still somewhat of an enigma. p53's intimate and multifaceted role in the cell cycle is mirrored in its equally complex structural biology that is being unraveled only slowly. Here, we discuss key structural aspects of p53 function and its inactivation by oncogenic mutations. Concerted action of folded and intrinsically disordered domains of the highly dynamic p53 protein provides binding promiscuity and specificity, allowing p53 to process a myriad of cellular signals to maintain the integrity of the human genome. Importantly, progress in elucidating the structural biology of p53 and its partner proteins has opened various avenues for structure-guided rescue of p53 function in tumors. These emerging anticancer strategies include targeting mutant-specific lesions on the surface of destabilized cancer mutants with small molecules and selective inhibition of p53's degradative pathways.

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p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells

Cited by 48 publications

References 36 publications

Myosin VI Is Differentially Regulated by DNA Damage in p53- and Cell Type-dependent Manners

Myosin VI Is Differentially Regulated by DNA Damage in p53- and Cell Type-dependent Manners

Mutant p53 Gain-of-Function in Cancer

The Tumor Suppressor p53: From Structures to Drug Discovery

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