Tumor inhibition by genomically integrated inducible RNAi-cassettes

Kappel, Sven; Matthess, Yves; Zimmer, Brigitte; Kaufmann, M.; Strebhardt, Klaus

doi:10.1093/nar/gkl628

Cited by 32 publications

(26 citation statements)

References 54 publications

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“…To investigate this correlation in more detail, we depleted cyclin B1 using our previously developed RNAi vectors (18,19,26,49). Because the complete small interfering RNA (siRNA)-mediated knockdown of cyclin B1 in our earlier studies induced apoptosis in a number of cancer cell types (49), we selected stable HeLa clones that exhibited only a partial knockdown of cyclin B1 (up to 80%) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Cdk1/Cyclin B1 Controls Fas-Mediated Apoptosis by Regulating Caspase-8 Activity

Matthess

Raab

Sanhaji

et al. 2010

Molecular and Cellular Biology

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Caspase activation is a hallmark of apoptosis. However, the molecular mechanisms underlying the regulation of caspase-8 activation within the extrinsic death pathway are not well understood. In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by Cdk1/cyclin B1 on Ser-387, which is located at the N terminus of the catalytic subunit p10. This phosphorylation of procaspase-8 on Ser-387 occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. Furthermore, RNA interferencemediated silencing of cyclin B1 or treatment with the Cdk1 inhibitor RO-3306 enhances the Fas-mediated activation and processing of procaspase-8 in mitotic cells. A nonphosphorylatable procaspase-8 (S387A) facilitates Fas-induced apoptosis during mitosis. Our findings suggest that Cdk1/cyclin B1 activity shields human cells against extrinsic death stimuli and unravel the molecular details of the cross talk between cell cycle and extrinsic apoptotic pathways. Finally, this new mechanism may also contribute to tumorigenesis.Intact apoptotic machinery is essential to maintain the integrity and homeostasis of multicellular organisms (8). The evasion of apoptosis is a hallmark of cancer, as demonstrated by the inability of cancer cells to respond appropriately to signals that normally control unrestricted growth (11). In mammalian cells, the apoptotic response is mediated by either the intrinsic or the extrinsic pathway, depending on the origin of the death stimulus. After stimulation of the death receptor Fas (APO-1/CD95) the death-inducing signaling complex (DISC) assembles, which contains the oligomerized receptor, the adaptor molecule FADD, two isoforms of procaspase-8 (procaspase-8a and -8b), procaspase-10, and c-Flip L/S/R (28, 37). In accordance with the induced proximity model, immediately after DISC formation, procaspase-8, which consists of two death effector domains (DED) and a protease domain containing the p18 and p10 subunits, is proteolytically processed (28). This autoprocessing follows a sequential order of events: while the first cleavage step occurs at Asp-374 and results in the formation of the subunits p43/p41 and p12, the second cleavage at Asp-216 and Asp-384 produces the enzymatically active subunits p18, p10, and the prodomain p26/p24 (5, 14, 27, 40). The mature caspase-8 heterotetramer p18 2 -p10 2 then translocates from the DISC to the cytosol, where it cleaves several substrates, such as Bid, and effector caspases to initiate the apoptotic cascade (22).Increasing evidence highlights the functional importance of procaspase-8 for carcinogenesis; several findings suggest that the impairment of procaspase-8 function by genetic and epigenetic mechanisms correlates with the malignant potential of different types of cancer (6,12,43,44). In the present study, we investigated the functional correlation of the cell cycle with the extrinsic death pathway. The cyclin-dependent kinase 1 (Cdk1) in complex with cyclin B1 (Cdk1/cyclin B1) is one of the key mitotic kinases. The kinase ac...

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Section: Resultsmentioning

confidence: 99%

Cdk1/Cyclin B1 Controls Fas-Mediated Apoptosis by Regulating Caspase-8 Activity

Matthess

Raab

Sanhaji

et al. 2010

Molecular and Cellular Biology

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“…[9][10][11][12][13][14][15] Since Plk1 expression is limited to proliferating cells, interference with Plk1 function results in apoptotic cell death in various tumor cells but not in normal cells. 6,10,12 Multiple lines of evidences have made Plk1 a promising target for the development of novel anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

Long-term downregulation of Polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21^WAF1/CIP1

Kreis¹,

Sommer²,

Sanhaji³

et al. 2009

Cell Cycle

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“…Díky této centrální roli v regulaci buněčného cyklu je Plk1 považována za vhodný cíl protinádo-rové terapie [74, [91][92][93][94][95][96][97]. Hluboká kavita ATP-vazebné domény kináz je obecným cílem návrhu ATP kompetitivních inhibitorů.…”

Section: Inhibitory Plk1unclassified

Polo-like Kinase 1 as a Target for Anti-tumor Therapy

Procházková¹,

Vojtěšek²

2015

Klin Onkol

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Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno SouhrnJednotlivé proteiny z rodiny polo-like kináz (Plk) plní rozdílné, avšak kritické funkce při regulaci buněčného cyklu a koordinují buněčnou odpověď na poškození DNA. Nejvíce prostudovaným z pěti členů této rodiny je protein Plk1. Jedná se o serin/ treonin kinázu, která hraje klíčovou roli v mnoha fázích mitózy, a s její deregulací se setkáváme u různých typů nádorů, kde je její zvýšená hladina většinou asociována s horší prognózou. Z pohledu léčby je také zajímavý vztah Plk1 a proteinu p53. Nejen z těchto důvodů se Plk1 stala jedním z atraktivních cílů pro vývoj protinádorových léčiv. Nejnadějněji se nyní jeví inhibitor ATP-vazebné oblasti Plk1 volasertib (BI 6727), který v doposud provedených klinických studiích prodloužil přežití pa cientů s akutní myeloidní leukemií a nyní je testován v klinické studii fáze III. Ve fázi preklinického testování se nachází také několik inhibitorů polo-box domény (druhého možného místa inhibice polo-like kináz), které by měly zajistit větší specifi tu vůči Plk1. Klíčová slovapolo-like kináza 1 -nádorový supresor p53 -ATP-kompetitivní inhibitory -polo-box doména -klinické studie SummaryIndividual proteins from polo-like kinase (Plk) family fulfi l diff erent but critical functions in regulating cell cycle and coordinate cell response to DNA-damage. The most studied one from this fi ve-member family is Plk1. It is a serine/ threonine kinase that plays a pivotal role in many aspects of mitosis and its deregulation is common in various tumor types where the elevated level is mostly associated with worse prognosis. From the therapeutical point of view, intertwin ed relationship between Plk1 and p53 protein is very interesting and will be discussed. Not only for these reasons, Plk1 has become an attractive target for anti-tumor drug development. The most promising seems to be ATP-binding site inhibitor Volasertib (BI 6727) which provided a survival benefi t for patients with acute myeloid leukemia and is now tested in phase III clinical trial. A new generation of Plk1 inhibitors that target the second druggable domain of Plk1, the polo-box domain, is currently being tested preclinically and are believed to improve Plk1 specifi city.

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Tumor inhibition by genomically integrated inducible RNAi-cassettes

Cited by 32 publications

References 54 publications

Cdk1/Cyclin B1 Controls Fas-Mediated Apoptosis by Regulating Caspase-8 Activity

Cdk1/Cyclin B1 Controls Fas-Mediated Apoptosis by Regulating Caspase-8 Activity

Long-term downregulation of Polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21^WAF1/CIP1

Polo-like Kinase 1 as a Target for Anti-tumor Therapy

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Tumor inhibition by genomically integrated inducible RNAi-cassettes

Cited by 32 publications

References 54 publications

Cdk1/Cyclin B1 Controls Fas-Mediated Apoptosis by Regulating Caspase-8 Activity

Cdk1/Cyclin B1 Controls Fas-Mediated Apoptosis by Regulating Caspase-8 Activity

Long-term downregulation of Polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21WAF1/CIP1

Polo-like Kinase 1 as a Target for Anti-tumor Therapy

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Long-term downregulation of Polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21^WAF1/CIP1