Microtubules as a target for anticancer drugs

Jordan, Mary Ann; Wilson, Leslie

doi:10.1038/nrc1317

Cited by 3,951 publications

(3,539 citation statements)

References 124 publications

Supporting

Mentioning

3,421

Contrasting

Unclassified

Order By: Relevance

“…In contrast, point mutant ( þ 2.F-I232A, þ 3.F-W260A, þ 5.C-I232A, þ 6C-W260A)-expressing cells showed the normal, high S/G2 population, supporting the notion that full-length RING105 protein delays/arrests cells in G1. Nocodazole is a spindle poison, activates the mitotic checkpoint and arrests cells in mitosis (Jordan and Wilson, 2004). As before, in the absence of drugs (Figure 4c, left panel), expression of RING105 full-length and of RING-finger domain in HeLa cells showed an increase in G1 population.…”

Section: Ring105 Expression Delays the G1-to-s Transition In Hela Cellssupporting

confidence: 67%

Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105

Yamada

Gorbsky

2005

Oncogene

View full text Add to dashboard Cite

The region of human chromosome 11p15.5 is linked with Beckwith-Wiedemann syndrome that is associated with susceptibility to Wilms' tumor, rhabdomyosarcoma and hepatoblastoma. TSSC5 (tumor-suppressing subchromosomal transferable fragment cDNA; also known as ORCTL2/IMPT1/BWR1A/SLC22A1L) is located in the region. The expression of TSSC5 and other genes in the region is regulated through paternal imprinting. Mutations and/or reduced expression of TSSC5 have been found in certain tumors. TSSC5 encodes an efflux transporter-like protein with 10 transmembrane domains, whose regulation may affect drug sensitivity, cellular metabolism and growth. Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop. Ectopic expression of RING105 in HeLa cells caused an accumulation of cells during G1 that was not observed with the expression of a form of RING105 in which a residue within the RING finger was mutated to inactivate its ligase activity. UbcH6-RING105 may define a novel ubiquitin-proteasome pathway that targets TSSC5 in mammalian cells.

show abstract

Section: Ring105 Expression Delays the G1-to-s Transition In Hela Cellssupporting

confidence: 67%

Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105

Yamada

Gorbsky

2005

Oncogene

View full text Add to dashboard Cite

show abstract

“…Of interest, microtubules appear to be a preferred target of naturally occurring cytotoxic substances produced by plants, including paclitaxel and vinca alkaloids [38]. Drugs that target microtubule often bind directly to tubulin; whether this is the case for cucurbitacins remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

Escandell

Kaler

Recio

et al. 2008

Biochemical Pharmacology

View full text Add to dashboard Cite

Cucurbitacins have been shown to inhibit proliferation in a variety of cancer cell lines. The aim of this study was to determine their biological activity in colon cancer cell lines that do not harbor activated STAT3, the key target of cucurbitacin. In order to establish the role of activated kRas in the responsiveness of cells to cucurbitacins, we performed experiments in isogenic colon cancer cell lines, HCT116 and Hke-3, which differ only by the presence of an activated kRas allele. We compared the activity of 23, 24-dihydrocucurbitacin B (DHCB) and cucurbitacin R (CCR), two cucurbitacins that we recently isolated, with cucurbitacin I (CCI), a cucurbitacin with established antitumorigenic activity. We showed that cucurbitacins induced dramatic changes in the cytoskeleton (collapse of actin and bundling of tubulin microfilaments), inhibited proliferation and finally induced apoptosis of both HCT116 and Hke3 cells. However, the presence of oncogenic k-Ras significantly decreased the sensitivity of cells to the three cucurbitacins tested, CCR, DHCB and CCI. We confirmed that mutational activation of kRas protects cells from cucurbitacin-induced apoptosis using nontransfromed intestinal epithelial cells with inducible expression of k-RasV12. Cucurbitacins induced the expression of p53 and p21 predominantly in HCT116 cells that harbor mutant Ras. Using HCT116 cells with targeted deletion of p53 or p21 we confirmed that p53 and p21 protect cells from apoptosis induced by cucurbitacins. These results demonstrated that sensitivity of human colon cancer cell lines to cucurbitacins depends on the kRas and p53/p21 status, and established that cucurbitacins can exert antitumorigenic activity in the absence of activated STAT3.

show abstract

“…The success of the tubulin targeting agents (such as vinca alkaloids and taxanes) led to acceptance of the hypothesis that drugs targeting other proteins of the mitotic spindle may be a rational strategy to combat tumor growth with the advantage of having less side effects [5,6]. Due toEg5's essential function in mitosis, it is now an important target for the development of inhibitors that have antimitotic activity [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

Tcherniuk

Lis

Kozielski

et al. 2010

Biochemical Pharmacology

View full text Add to dashboard Cite

. Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-Trityl-L-Cysteine in tumor derived cell lines.. Biochemical Pharmacology, Elsevier, 2010, 79 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. confirms the target specificity of monastrol and STLC for Eg5. These data also suggest a possible mechanism by which drug resistance may occur in tumors treated with agents targeting Eg5.

show abstract

Microtubules as a target for anticancer drugs

Cited by 3,951 publications

References 124 publications

Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105

Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

Contact Info

Product

Resources

About