Self-Renewal Versus Lineage Commitment of Embryonic Stem Cells: Protein Kinase C Signaling Shifts the Balance

Dutta, Debasree; Ray, Soma; Home, Pratik; Larson, Melissa A.; Wolfe, Michael W.; Paul, Soumen

doi:10.1002/stem.605

Cited by 81 publications

(83 citation statements)

References 41 publications

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“…Interestingly, earlier reports implicated atypical PKC signaling in regulating NF-kB p65 (RelA) function in multiple cell types, 49,50 and RelA has a known association with various cytokine networks 51,52 (Supplementary Figure S7b). As RelA is one of the major transcription factors that inhibited upon PKCl/i depletion in MDA-MB-231 cells (as predicted by IPA in Supplementary Table S3), we tested RelA expression in multiple TNBC cells along with HER2-positive BT474 and ER þ MCF-7 cells.…”

Section: Resultsmentioning

confidence: 98%

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

et al. 2014

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Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCk/i, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCk/i signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCk/i signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCk/i expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCk/i significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCk/i-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFb and IL1b could activate PKCk/i signaling in TNBC cells and depletion of PKCk/i impairs NF-jB p65 (RelA) nuclear localization. We observed that cytokine-PKCk/i-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCk/i promote TNBC growth, invasion and metastasis. Thus, targeting PKCk/i signaling could be a therapeutic option for breast cancer, including the TNBC subtype.

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Section: Resultsmentioning

confidence: 98%

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

et al. 2014

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“…HEK293T (a gift from Dr Soumen Paul, University of Kansas Medical Center) and MEFs were cultured in standard medium, as reported previously (Dutta et al, 2011). E14 ESCs were cultured in feeder-free conditions in ES culture medium (Dutta et al, 2011) and were a gift from Dr. Jay L Vivian (University of Kansas Medical Center).…”

Section: Cell Culturementioning

confidence: 99%

“…E14 ESCs were cultured in feeder-free conditions in ES culture medium (Dutta et al, 2011) and were a gift from Dr. Jay L Vivian (University of Kansas Medical Center).…”

Section: Cell Culturementioning

confidence: 99%

“…Uterine horns were removed, and embryos collected, finely minced and incubated with 0.25% trypsin for 30 min to complete the digestion. Trypsin was inactivated by adding MEF medium, and suspensions were centrifuged at a low speed, and supernatant was collected and cultured in MEF medium (Dutta et al, 2011).…”

Section: Isolation Of Mouse Embryonic Fibroblastsmentioning

confidence: 99%

“…Induced pluripotent stem cells were generated using a lentiviral-based polycistronic vector (FUW-TetO-OSKM; Addgene; 20321) carrying OSKM under the control of a doxycycline-inducible TetO operator (Tet) (Carey et al, 2009;Dutta et al, 2011). MEFs were infected with concentrated lentiviral particles expressing OSKM and Tet.…”

Section: Generation Of Ipscsmentioning

confidence: 99%

See 2 more Smart Citations

Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts

Syed¹,

Joseph²,

Mukherjee³

et al. 2017

Development

Self Cite

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The authors apologise to the readers for any confusion that this error might have caused. For the first time, we report here that the downregulation of histone chaperone Aprataxin PNK-like factor (APLF) promotes reprogramming by augmenting the expression of E-cadherin (Cdh1), which is implicated in the mesenchymal-to-epithelial transition (MET) involved in the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs). Downregulation of APLF in MEFs expedites the loss of the repressive MacroH2A.1 (encoded by H2afy) histone variant from the Cdh1 promoter and enhances the incorporation of active histone H3me2K4 marks at the promoters of the pluripotency genes Nanog and Klf4, thereby accelerating the process of cellular reprogramming and increasing the efficiency of iPSC generation. We demonstrate a new histone chaperone (APLF)-MET-histone modification cohort that functions in the induction of pluripotency in fibroblasts. This regulatory axis might provide new mechanistic insights into perspectives of epigenetic regulation involved in cancer metastasis.

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Propagating pluripotency – The conundrum of self‐renewal

Smith

2024

BioEssays

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The discovery of mouse embryonic stem cells in 1981 transformed research in mammalian developmental biology and functional genomics. The subsequent generation of human pluripotent stem cells (PSCs) and the development of molecular reprogramming have opened unheralded avenues for drug discovery and cell replacement therapy. Here, I review the history of PSCs from the perspective that long‐term self‐renewal is a product of the in vitro signaling environment, rather than an intrinsic feature of embryos. I discuss the relationship between pluripotent states captured in vitro to stages of epiblast in the embryo and suggest key considerations for evaluation of PSCs. A remaining fundamental challenge is to determine whether naïve pluripotency can be propagated from the broad range of mammals by exploiting common principles in gene regulatory architecture.

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Self-Renewal Versus Lineage Commitment of Embryonic Stem Cells: Protein Kinase C Signaling Shifts the Balance

Cited by 81 publications

References 41 publications

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts

Propagating pluripotency – The conundrum of self‐renewal

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