1,721,196 research outputs found
Coordinating proteolysis with mitotic spindle assembly: mechanisms for chromosomal stability.
No full textNew insights on oxidative stress in cancer.
No full textCancer initiation and progression has been linked to oxidative stress, a condition in which the balance between production and disposal of reactive oxygen or nitrogen species is altered. Oxidative stress has several protumorigenic effects, such as increasing DNA mutation rate or inducing DNA damage, genome instability and cell proliferation. Conversely, oxidative stress also exerts antitumorigenic actions, and it is has been linked to senescence and apoptosis, two major mechanisms that counteract tumor development. In this review, recent findings that relate oxidative stress to cancer-associated conditions, such as chronic inflammation, steroid hormone signaling and altered chromosome segregation, are highlighted, and how these studies may identify new targets for the development of drugs and strategies for cancer prevention and cure is discussed
Attach first, then detach: a role for cyclin B-dependent kinase 1 in coordinating proteolysis with spindle assembly.
No full textRequirement for proteolysis in spindle assembly checkpoint silencing.
No full textAnaphase initiation requires ubiquitin-dependent proteolysis of crucial substrates through activation of the ubiquitin ligase Anaphase promoting Complex/Cyclosome (ApC/C) in association with its coactivator Cdc20. To prevent chromosome segregation errors, effector proteins of a safeguard mechanism called spindle assembly checkpoint (SAC), Mad2 and BubR1, bind Cdc20 and restrain ApC/C(Cdc20) activation until spindle assembly. Coordinated chromosome segregation also requires timely SAC inactivation. Spindle assembly appears necessary to silence SAC, however, how resolution of the SAC effector branch is achieved is still largely unknown. We show here that the complex between Mad2 and Cdc20 peaked at prometaphase in mammalian cells, while its dissociation proceeded along with spindle assembly and required proteolysis. proteolysis did not appear required for assembly of metaphase spindles but rather needed for Mad2-Cdc20 complex resolution by promoting reversal of phosphorylations that maintain the complex. Indeed, in the absence of proteolysis, Mad2-Cdc20 complex dissociation was reversed by treatment with cyclin-dependent kinase or Aurora kinase inhibitors. Mad2-Cdc20 disassembly was, however, resistant to the potent pp1 and pp2A phosphatases inhibitor okadaic acid. We propose that SAC silencing in mammalian cells requires proteolysis-dependent activation of okadaic acid-resistant phosphatase(s) to reverse phosphorylations that lock the Mad2-Cdc20 complex
Oxidative stress overrides the spindle checkpoint
No full textAneuploidy, an abnormal chromosome set, can ensue from failure of the spindle checkpoint, the safeguard mechanism that halts anaphase onset until mitotic spindle assembly. Inefficiency of cells to maintain the normal chromosome set across cell generations has been linked to tumorigenesis and senescence. Here we show that oxidative stress overrides the spindle checkpoint mechanism. Oxidant challenge of checkpoint-arrested cells led to proteolysis of the anaphase inhibitor securin and mitotic cyclins. This appeared consequent to loss of cyclin B-cdk1 activity caused by oxidant-induced reversal of cdk1 inhibitory phosphorylation. These observations may provide a link between aneuploidy occurrence and oxidative stress
cGAS-dependent proinflammatory and immune homeostatic effects of the microtubule-targeting agent paclitaxel
Full text link: Taxanes are Microtubule-Targeting Agents (MTAs) that exert potent anticancer activity by directly killing cancer cells. However, recent evidence suggests that they may also stimulate inflammation and anticancer adaptive immunity and that these actions strongly contribute to their therapeutic efficacy. Details on how Taxanes may modulate inflammation and anticancer immunity are, nevertheless, still missing. We show here that at very low doses the Taxane Paclitaxel (Pxl) indeed induces a potent proinflammatory response in various cancer cell types in a cyclic GMP-AMP (cGAMP) synthase (cGAS)- and Stimulator of Interferon Genes (STING)-dependent manner, leading to interferon (IFN) signaling. However, we find that Pxl treatment also strongly upregulates the expression of the immune checkpoint protein Programmed Death-Ligand 1 (PD-L1) in cancer cells, therefore, inducing an inhibitory response to adaptive immunity potentially attenuating anticancer immunity and therapeutic success. These observations provide a mechanistic explanation of why clinical benefit may derive from the combination of Pxl with Immune Checkpoint Inhibitors (ICIs) and suggest that more accurately tailoring dosage and schedule of this combination therapy may provide benefit in the management of a larger number of cancer types and stages
A Word of Caution on the Danger of Noninvasive Respiratory Support During Sepsis
No full textWe read with great interest the recently published study by Xu et al (1)
in Critical Care Medicine. Among immunocompromised patients
with sepsis requiring respiratory support, the authors demonstrated
that prolonged noninvasive ventilation (NIV) before transition to invasive mechanical
ventilation was associated to higher risk of in-hospital mortality. The
risk increased in NIV patients who experienced longer time to intubation, suggesting
a dose-response relationship
Sustaining the Spindle Assembly Checkpoint to improve cancer therapy
Full text linkTo prevent chromosome segregation errors, the spindle assembly checkpoint (SAC) delays mitosis exit until proper spindle assembly. We found that the FCP1 phosphatase and its downstream target WEE1 kinase oppose the SAC, promoting mitosis exit despite malformed spindles. We further showed that targeting this pathway might be useful for cancer therapy
On the assembly of the mitotic spindle, bistability and hysteresis
Full text link: During cell division, the transition from interphase to mitosis is dictated by activation of the cyclin B-cdk1 (Cdk1) complex, master mitotic kinase. During interphase, Cdk1 accumulates in an inactive state (pre-Cdk1). When Cdk1 overcomes a certain threshold of activity upon initial activation of pre-Cdk1, then the stockpiled pre-Cdk1 is rapidly converted into overshooting active Cdk1, and mitosis is established irreversibly in a switch-like fashion. This is granted by positive Cdk1 activation loops and the concomitant inactivation of Cdk1 counteracting phosphatases, empowering Cdk1 activity and favoring the Cdk1-dependent phosphorylations that are required to establish mitosis. These circuitries prevent backtracking and ensure unidirectionality so that interphase and mitosis are considered bistable states. Mitosis also shows hysteresis, meaning that the levels of Cdk1 activity needed to establish mitosis are higher than those required to maintain it; therefore, once in mitosis cells can tolerate moderate drops in Cdk1 activity without exiting mitosis. Whether these features have other functional implications in addition to the general action of preventing backtracking is unknown. Here, we contextualize these concepts in the view of recent evidence indicating that loss of activity of small and compartmentalized amounts of Cdk1 within mitosis is necessary to assemble the mitotic spindle, the structure required to segregate replicated chromosomes. We further propose that, in addition to prevent backtracking, the stability and hysteresis properties of mitosis are also essential to move forward in mitosis by allowing cells to bear small, localized, drops in Cdk1 activity that are necessary to build the mitotic spindle
Fighting tubulin-targeting anticancer drug toxicity and resistance
No full textTubulin-targeting drugs, like taxanes and vinca alkaloids, are among the most effective anticancer therapeutics used in the clinic today. Specifically, anti-microtubule cancer drugs (AMCDs) have proven to be effective in the treatment of castration-resistant prostate cancer and triple-negative breast cancer. AMCDs, however, have limiting toxicities that include neutropenia and neurotoxicity, and, in addition, tumor cells can become resistant to the drugs after long-term use. Co-targeting mitotic progression/slippage with inhibition of the protein kinases WEE1 and MYT1 that regulate CDK1 kinase activity may improve AMCD efficacy, reducing the acquisition of resistance by the tumor and side effects from the drug and/or its vehicle. Other possible treatments that improve outcomes in the clinic for these two drug-resistant cancers, including new formulations of the AMCDs and pursuing different molecular targets, will be discussed
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