A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation

Restelli, Michela; Magni, Martina; Ruscica, Vincenzo; Pinciroli, Patrizia; Cecco, Loris De; Buscemi, Giacomo; Delia, Domenico; Zannini, Laura

doi:10.1038/cddis.2016.359

Cited by 24 publications

(21 citation statements)

References 37 publications

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“…Importantly, CCAR2 is a core component of the DBIRD complex, a multiprotein complex, which acts at the interface between core messenger RNP particles and RNA polymerase II, and integrates transcript elongation with regulation of alternative splicing [34]. CCAR2 depletion could affect the anchorage-independent growth of several types of cancer cells [35]. Taking these data into account, and on the basis of our present data, we hypothesize that CCAR2, which is present at high levels even in ESRP1-negative cells such as COLO320DM, can perform its multiplicity of function, independent of ESRP1.…”

Section: Discussionmentioning

confidence: 99%

Proteomics-Based Evidence for a Pro-Oncogenic Role of ESRP1 in Human Colorectal Cancer Cells

Ala

Manco

Mandili

et al. 2020

IJMS

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The RNA-binding protein, Epithelial Splicing Regulatory Protein 1 (ESRP1) can promote or suppress tumorigenesis depending on the cell type and disease context. In colorectal cancer, we have previously shown that aberrantly high ESRP1 expression can drive tumor progression. In order to unveil the mechanisms by which ESRP1 can modulate cancer traits, we searched for proteins affected by modulation of Esrp1 in two human colorectal cancer cell lines, HCA24 and COLO320DM, by proteomics analysis. Proteins hosted by endogenous ESRP1 ribonucleoprotein complex in HCA24 cells were also analyzed following RNA-immunoprecipitation. Proteomics data were complemented with bioinformatics approach to exploit publicly available data on protein-protein interaction (PPI). Gene Ontology was analysed to identify a common molecular signature possibly explaining the pro-tumorigenic role of ESRP1. Interestingly, proteins identified herein support a role for ESRP1 in response to external stimulus, regulation of cell cycle and hypoxia. Our data provide further insights into factors affected by and entwined with ESRP1 in colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Proteomics-Based Evidence for a Pro-Oncogenic Role of ESRP1 in Human Colorectal Cancer Cells

Ala

Manco

Mandili

et al. 2020

IJMS

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“…CCAR2, a widely expressed protein, is required for cell proliferation and is associated with poor prognosis in squamous cell carcinoma [52]. CCAR2 silencing decreases cell proliferation by altering the AKT pathway [53]. Two studies have indicated that CCAR2 interacts with HSP60 and survivin to form a CCAR2-HSP60-survivin complex in mitochondria.…”

Section: Interaction Between Hsp60 and Survivin In Mitochondriamentioning

confidence: 99%

Functional Compartmentalization of HSP60-Survivin Interaction between Mitochondria and Cytosol in Cancer Cells

Huang

Yeh

2019

Cells

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Heat shock protein 60 (HSP60) and survivin reside in both the cytosolic and mitochondrial compartments under physiological conditions. They can form HSP60-survivin complexes through protein-protein interactions. Their expression levels in cancer tissues are positively correlated and higher expression of either protein is associated with poor clinical prognosis. The subcellular location of HSP60-survivin complex in either the cytosol or mitochondria is cell type-dependent, while the biological significance of HSP60-survivin interaction remains elusive. Current knowledge indicates that the function of HSP60 partly rests on where HSP60-survivin interaction takes place. HSP60 has a pro-survival function when binding to survivin in the mitochondria through interacting with other factors such as CCAR2 and p53. In response to cell death signals, mitochondrial survivin functions through preventing procaspase activation. Degradation of cytosolic survivin leads to the loss of mitochondrial membrane potential and aberrant mitosis processes. On the other hand, HSP60 release from mitochondria to cytosol upon death stimuli might exert a pro-death function, either through stabilizing Bax, enhancing procaspase-3 activation, or increasing protein ubiquitination. Combining the knowledge of mitochondrial HSP60-survivin complex function, cytosolic survivin degradation effect, and pro-death function upon mitochondria release of HSP60, a hypothetical scenario for HSP60-survivin shuttling upon death stimuli is proposed.

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“…LKB1 negatively regulates AKT1 via DBC1 and TRB3. DBC1 is known to act as a positive regulator of AKT1 S473 phosphorylation via Tribbles3 (TRB3) (11). It does so by transcriptional repression of TRB3 expression.…”

Section: Pyst Induces Energy Deficit and Activates Lkb1-ampk Pathway:mentioning

confidence: 99%

“…Activated LKB1, through an unknown mechanism, leads to the degradation of DBC1 protein. DBC1 is a transcriptional co-repressor for TRB3 expression (11). In the absence of growth factors, Tribbles3 is known to sequester AKT1 and prevent its phosphorylation and activation by upstream kinases (11,12).…”

Section: Energy Deficit Is Critical For the Induction Of Mitotic Arrementioning

confidence: 99%

“…DBC1 is a transcriptional co-repressor for TRB3 expression (11). In the absence of growth factors, Tribbles3 is known to sequester AKT1 and prevent its phosphorylation and activation by upstream kinases (11,12). Since activated LKB1 degrades DBC1, this would mean upregulation of TRB3 expression and consequent inactivation of AKT1.…”

Section: Energy Deficit Is Critical For the Induction Of Mitotic Arrementioning

confidence: 99%

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LKB1 negatively regulates AKT1 signaling via DBC1 and TRB3

Sarwar

Bhat

Gillani

et al. 2019

Preprint

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DBC1 plays a critical role in various cellular functions notably cell proliferation, transcription, histone modification and adipogenesis. Current reports about the role of DBC1 in tumorigenesis areparadoxical and designate DBC1 both as a tumor suppressor or an oncogene. Here, using small T antigen of polyoma virus (PyST) as a tool, we have delineated a signaling mechanism that connects LKB1 to AKT1 via DBC1. We report that PyST associates with DBC1 and leads to its down- regulation. Our results also show that PyST expression promotes LKB1 activation which in turn leads to in the downregulation of DBC1 protein. Absence of DBC1 results in transcriptional upregulationand consequently enhanced protein levels of TRB3. TRB3 sequesters AKT1, and consequently the phosphorylation and activity of AKT1 is compromised. This ultimately results in inactivation of prosurvival pathways triggered via AKT1 signaling. Our studies thus provide an insight into a signaling pathway that connects LKB1, DBC1, TRB3 and AKT1.Running title: DBC1 regulates signaling from LKB1 to AKT.

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A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation

Cited by 24 publications

References 37 publications

Proteomics-Based Evidence for a Pro-Oncogenic Role of ESRP1 in Human Colorectal Cancer Cells

Proteomics-Based Evidence for a Pro-Oncogenic Role of ESRP1 in Human Colorectal Cancer Cells

Functional Compartmentalization of HSP60-Survivin Interaction between Mitochondria and Cytosol in Cancer Cells

LKB1 negatively regulates AKT1 signaling via DBC1 and TRB3

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