The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer

Dillon, Rachelle L.; White, Donald E.; Muller, William J.

doi:10.1038/sj.onc.1210202

Cited by 266 publications

(256 citation statements)

References 77 publications

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“…IRS-4 has previously been shown to increase proliferation in non-stimulated cells (Qu et al, 1999). The deregulation of PI3 kinase and Akt signalling plays a major part in cellular transformation and cancer progression (Dillon et al, 2007). Although mRNA is limited to only a few normal human cell types, increased levels have been detected in some carcinoma cells, including HEP-2 and A431 cells, whereas IRS-4 protein has been found to be endogenously expressed in A431 and MDA-MB 231 tumour cells (Qiu et al, 2005), indicating that the deregulation of this gene in the absence of Ad5E1A might play an important role in tumourigenesis.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

et al. 2008

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Using mass spectrometric analysis insulin receptor substrate 4 (IRS-4) has been identified as a novel adenovirus 5 early region 1A (Ad5E1A)-binding protein. IRS-4 interacts with both the transcriptional activation domain (conserved region 3) and the N-terminal region of Ad5E1A13S. Prolonged expression of Ad5E1A13S is required for the observed dramatic increase in the levels of IRS-4 mRNA and protein in Ad5E1-transformed human cell lines. Once expressed, as well as binding to E1A and the insulin receptor, IRS-4 remains tyrosine phosphorylated and constitutively associates with the regulatory p85 subunit of phosphoinositide 3 kinase, resulting in the phosphorylation of Akt (causing activation) and GSK-3b (causing inhibition). Reducing IRS-4 expression using small interfering RNA (siRNA) in established Ad5E1A-expressing cell lines decreases the activation of Akt and cellular proliferation. During Ad5 infection, IRS-4 is not expressed. However, Ad5E1A associates with IRS-1, increasing Akt and GSK-3b phosphorylation and tyrosine phosphorylation of IRS-1 itself. We conclude that the association and altered regulation of IRS proteins by Ad5E1A contribute to the adenovirus-transformed phenotype and modulates viral infection in an Akt-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

et al. 2008

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“…22 Membrane recruitment and binding to PtdIns (3,4,5)P3 causes conformational changes in Akt, resulting in exposure of its phoshorylation sites T308 and S473 which are then phosphorylated by phosphoinositide dependent kinase (PDK) and mammalian target of rapamycin (mTOR)/rictor, respectively. 23,24 Thus, the activated (phosphorylated) Akt stays mostly in the cytoplasm. However, under certain conditions it may also be transferred into the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

et al. 2015

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Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44 CHigh /CD24 ¡Low phenotype. This effect was completely reversed in the presence of Aktspecific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21 Waf1/Cip1 and exhibited increased clonogenicity and proliferation as assayed by colony-forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. Summary: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells.

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“…10 This has made Akt a major target for cancer drug discovery. [12][13][14][15] There are three mammalian Akt isoforms that may play distinct but also overlapping roles in development, normal physiology and tumorigenesis. For example, in mice, loss of Akt1 function results in smaller body size and significant growth defects.…”

Section: Introductionmentioning

confidence: 99%

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Berndt¹,

Patel²,

Yang³

et al. 2013

Cell Cycle

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The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer

Cited by 266 publications

References 77 publications

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

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The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer

Cited by 266 publications

References 77 publications

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21Waf1/Cip1and p27kip1

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

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Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1