Interaction of DBC1 with polyoma small T antigen promotes its degradation and negatively regulates tumorigenesis

Sarwar, Zarka; Nabi, Nusrat; Bhat, Sameer Ahmed; Gillani, Syed Qaaifah; Reshi, Irfana; Nisa, Misbah Un; Adelmant, Guillaume; Marto, Jarrod A.; Andrabi, Shaida

doi:10.1016/j.jbc.2021.101496

Cited by 3 publications

(4 citation statements)

References 63 publications

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“…To validate that this interaction of PP2A subunits is specific to PCTAIRE1, we also probed DBC1 (also known as CCAR2) and SIRT1 in the same experiment. This was relevant, as our other studies have shown that PolST interacts with DBC1, which consequently affects its association with SIRT1 deacetylase ( Sarwar et al, 2022 ). Our results did not show any such interaction between PCTAIRE1 and these proteins, thus confirming that the interaction between PCTAIRE1 and PP2A subunits is specific.…”

Section: Resultsmentioning

confidence: 84%

PCTAIRE1 promotes mitotic progression and resistance against antimitotic and apoptotic signals

Gillani

Reshi

Nabi

et al. 2022

Journal of Cell Science

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PCTAIRE1 is a serine-threonine kinase implicated in physiological processes like neuronal development, vesicle trafficking, spermatogenesis, and cell proliferation. However, its exact role in cell division remains unclear. In this study, using a library screening approach, we identified PCTAIRE1 among several candidates that resisted mitotic arrest and mitotic cell death induced by polyoma virus small T (PolST) expression. Our study showed that PCTAIRE1 is a mitotic kinase that localizes at centrosomes during G2 and at spindle poles as the cells enter mitosis, and then at midbody during cytokinesis. We also report that PCTAIRE1 protein levels fluctuate through cell cycle, and reach their peak at mitosis, during which there is an increase in PCTAIRE1 phosphorylation as well. Interestingly, knockdown of PCTAIRE1 resulted in aberrant mitosis by interfering with spindle assembly and chromosome segregation. Further, we found that PCTAIRE1 promotes resistance of cancer cells to antimitotic drugs, thus underscoring the significance of PCTAIRE1 as a potential drug target for overcoming chemotherapeutic resistance. Taken together, these studies establish PCTAIRE1 as a critical mediator of mitotic progression and highlight its role in chemotherapeutic resistance.

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Section: Resultsmentioning

confidence: 84%

PCTAIRE1 promotes mitotic progression and resistance against antimitotic and apoptotic signals

Gillani

Reshi

Nabi

et al. 2022

Journal of Cell Science

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“…The LKB1‐AMP kinase axis negatively regulates this pathway through the phosphorylation and activation of TSC1/2 complex (Inoki et al 2003). In addition, we have also found out that AKT1 and LKB1 regulate protein levels of some proteins (e.g DBC1/CCAR2 and PCTAIRE1/CDK16) in contrasting ways (Gillani et al 2022; Sarwar et al 2022). We therefore tested the effect of LKB1 on lipin‐1 protein levels.…”

Section: Resultsmentioning

confidence: 97%

Lipin-1 stability and its adipogenesis functions are regulated in contrasting ways by AKT1 and LKB1

Nisa

Gillani

Nabi

et al. 2022

J. Cell Commun. Signal.

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Lipin‐1 is a protein that plays a critical role in many cellular functions. At molecular level, it acts as a phosphatidic acid phosphohydrolase and a transcriptional coactivator. The functions of lipin‐1 are largely dependent upon its subcellular localization, post‐translational modifications like phosphorylation and acetylation, and also on its interaction with other proteins such as 14‐3‐3. However, the kinases and phosphatases that are responsible for these post translational modifications are not entirely known. Using bioinformatics and other biochemical approaches, we demonstrate lipin‐1 as a novel target for AKT1 and LKB1. While AKT1 stabilizes lipin‐1, LKB1 causes its degradation. Interestingly, our findings further show that lipin‐1 enhances AKT1 activity as can be seen by increased phosphorylation of the substrates of AKT1. Taken together, our results suggest that lipin‐1 plays an important role in the regulation of PI3K‐AKT‐mTOR pathway, which is dysregulated in majority of cancers. Therefore, understating the role of lipin‐1 may provide new and important insights into the regulation and functions of the PI3K‐mTOR pathway, which is one of the major targets for anti‐cancer drug development strategies.

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“…Our study demonstrates that CCAR2 is one of the regulatory proteins for mitotic progression. Sarwar et al showed that CCAR2 is localized to nucleoplasm during interphase, to spindle poles during prometaphase and metaphase, to midzone during anaphase, and midbody during telophase and cytokinesis [ 18 ]. However, we observed that CCAR2 is leaked to cytoplasmic region after nuclear envelope breakdown and re-localized in nucleoplasm after nuclear membrane assembly during mitotic phase.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, CCAR2 is required for the expression of a subset of cell cycle-regulated genes in human squamous cell carcinoma cells [ 17 ]. A recent report also showed that CCAR2 is required for exit from polyoma small T (PyST)-induced mitotic arrest [ 18 ]. Although a role for CCAR2 in regulating mitosis has been suggested, no study has reported the direct role of CCAR2 in mitosis.…”

Section: Introductionmentioning

confidence: 99%

CCAR2 controls mitotic progression through spatiotemporal regulation of Aurora B

Ryu

Kim

2022

Cell Death Dis

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CCAR2 (cell cycle and apoptosis regulator 2) is a multifaceted protein involved in cell survival and death following cytotoxic stress. However, little is known about the physiological functions of CCAR2 in regulating cell proliferation in the absence of external stimuli. The present study shows that CCAR2-deficient cells possess multilobulated nuclei, suggesting a defect in cell division. In particular, the duration of mitotic phase was perturbed. This disturbance of mitotic progression resulted from premature loss of cohesion with the centromere, and inactivation of the spindle assembly checkpoint during prometaphase and metaphase. It resulted in the formation of lagging chromosomes during anaphase, leading ultimately to the activation of the abscission checkpoint to halt cytokinesis. The CCAR2-dependent mitotic progression was related to spatiotemporal regulation of active Aurora B. In conclusion, the results suggest that CCAR2 governs mitotic events, including proper chromosome segregation and cytokinetic division, to maintain chromosomal stability.

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Interaction of DBC1 with polyoma small T antigen promotes its degradation and negatively regulates tumorigenesis

Cited by 3 publications

References 63 publications

PCTAIRE1 promotes mitotic progression and resistance against antimitotic and apoptotic signals

PCTAIRE1 promotes mitotic progression and resistance against antimitotic and apoptotic signals

Lipin-1 stability and its adipogenesis functions are regulated in contrasting ways by AKT1 and LKB1

CCAR2 controls mitotic progression through spatiotemporal regulation of Aurora B

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