CA224, a non-planar analogue of fascaplysin, inhibits Cdk4 but not Cdk2 and arrests cells at G0/G1 inhibiting pRB phosphorylation

Mahale, Sachin; Aubry, Carine; Wilson, A. James; Jenkins, Paul R.; Maréchal, Jean‐Didier; Sutcliffe, Michael J.; Chaudhuri, Bhabatosh

doi:10.1016/j.bmcl.2006.05.065

Cited by 27 publications

(21 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This novel action was accompanied by and related to down-regulation of Cyclin D1 and its partners Cdk4, Cdk6, and Cdk2. The interaction between Cyclin D1 and its partners, especially Cdk4, is vital during the G1 phase, and disruption of either Cyclin D1 or Cdk4 can induce G0/G1 arrest [25-27]. …”

Section: Discussionmentioning

confidence: 99%

HSP90 inhibitor, celastrol, arrests human monocytic leukemia cell U937 at G0/G1 in thiol-containing agents reversible way

Peng

Cao

et al. 2010

Mol Cancer

View full text Add to dashboard Cite

BackgroundBecause some of heat shock protein 90's (HSP90) clients are key cell cycle regulators, HSP90 inhibition can affect the cell cycle. Recently, celastrol is identified both as a novel inhibitor of HSP90 and as a potential anti-tumor agent. However, this agent's effects on the cell cycle are rarely investigated. In this study, we observed the effects of celastrol on the human monocytic leukemia cell line U937 cell cycle.ResultsCelastrol affected the proliferation of U937 in a dose-dependent way, arresting the cell cycle at G0/G1 with 400 nM doses and triggering cell death with doses above 1000 nM. Cell cycle arrest was accompanied by inhibition of HSP90 ATPase activity and elevation in HSP70 levels (a biochemical hallmark of HSP90 inhibition), a reduction in Cyclin D1, Cdk4 and Cdk6 levels, and a disruption of the HSP90/Cdc37/Cdk4 complex. The observed effects of celastrol on the U937 cell cycle were thiol-related, firstly because the effects could be countered by pre-loading thiol-containing agents and secondly because celastrol and thiol-containing agents could react with each other to form new compounds.ConclusionsOur results disclose a novel action of celastrol-- causing cell cycle arrest at G0/G1 phase based upon thiol-related HSP90 inhibition. Our work suggests celastrol's potential in tumor and monocyte-related disease management.

show abstract

Section: Discussionmentioning

confidence: 99%

HSP90 inhibitor, celastrol, arrests human monocytic leukemia cell U937 at G0/G1 in thiol-containing agents reversible way

Peng

Cao

et al. 2010

Mol Cancer

View full text Add to dashboard Cite

show abstract

“…Fascaplysin (FASC) is a naturally derived molecule isolated from a marine sponge which specifically inhibits the interaction between cdk4/Cyclin D at an IC 50 of approximately 0.35 μM, and to a lesser extent cdk6/Cyclin D by binding the ATP pocket of cdk4, resulting in cell cycle arrest at G1/S [52,53]. Again, we treated latently infected HIV-1 cell lines (J1.1 and U1) with three concentrations of FASC (100 nM, 500 nM, and 1 μM) and collected supernatants at 24, 48, and 72 hours post treatment.…”

Section: Resultsmentioning

confidence: 99%

Interview: Malaria control: learning from the past to create a better future

Nájera¹

2010

Therapy

View full text Add to dashboard Cite

show abstract

“…In order to confirm that the cellular effects shown in Figure 4 are specific to the natural biological activity of p16 INK4A as a cdk4/6/Cyclin D inhibitor, we attempted to mimic these studies with the small molecule compound inhibitor Fascaplysin. Fascaplysin (FASC) is a naturally derived molecule isolated from a marine sponge which specifically inhibits the interaction between cdk4/Cyclin D at an IC 50 of approximately 0.35 μM, and to a lesser extent cdk6/Cyclin D by binding the ATP pocket of cdk4, resulting in cell cycle arrest at G1/S [52,53]. Again, we treated latently infected HIV-1 cell lines (J1.1 and U1) with three concentrations of FASC (100 nM, 500 nM, and 1 μM) and collected supernatants at 24, 48, and 72 hours post treatment.…”

Section: Fascaplysin Treatment Mimics the Exogenous P16 Ink4a Treatmentmentioning

confidence: 99%

The identification of unique serum proteins of HIV-1 latently infected long-term non-progressor patients

et al. 2010

View full text Add to dashboard Cite

BackgroundThe search for disease biomarkers within human peripheral fluids has become a favorable approach to preventative therapeutics throughout the past few years. The comparison of normal versus disease states can identify an overexpression or a suppression of critical proteins where illness has directly altered a patient's cellular homeostasis. In particular, the analysis of HIV-1 infected serum is an attractive medium with which to identify altered protein expression due to the ease and non-invasive methods of collecting samples as well as the corresponding insight into the in vivo interaction of the virus with infected cells/tissue. The utilization of proteomic techniques to globally identify differentially expressed serum proteins in response to HIV-1 infection is a significant undertaking that is complicated due to the innate protein profile of human serum.ResultsHere, the depletion of 12 of the most abundant serum proteins, followed by two-dimensional gel electrophoresis coupled with identification of these proteins using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, has allowed for the identification of differentially expressed, low abundant serum proteins. We have analyzed and compared serum samples from HIV-1 infected subjects who are being treated using highly active antiretroviral therapy (HAART) to those who are latently infected but have not progressed to AIDS despite the absence of treatment, i.e. long term non-progressors (LTNPs). Here we have identified unique serum proteins that are differentially expressed in LTNP HIV-1 patients and may contribute to the ability of these patients to combat HIV-1 infection in the absence of HAART. We focused on the cdk4/6 cell cycle inhibitor p16INK4A and found that the treatment of HIV-1 latently infected cell lines with p16INK4A decreases viral production despite it not being expressed endogenously in these cells.ConclusionsIdentification of these unique proteins may serve as an indication of altered viral states in response to infection as well as a natural phenotypic variability in response to HIV-1 infection in a given population.

show abstract

CA224, a non-planar analogue of fascaplysin, inhibits Cdk4 but not Cdk2 and arrests cells at G0/G1 inhibiting pRB phosphorylation

Cited by 27 publications

References 15 publications

HSP90 inhibitor, celastrol, arrests human monocytic leukemia cell U937 at G0/G1 in thiol-containing agents reversible way

HSP90 inhibitor, celastrol, arrests human monocytic leukemia cell U937 at G0/G1 in thiol-containing agents reversible way

Interview: Malaria control: learning from the past to create a better future

The identification of unique serum proteins of HIV-1 latently infected long-term non-progressor patients

Contact Info

Product

Resources

About