KLF4 Nuclear Export Requires ERK Activation and Initiates Exit from Naive Pluripotency

Dhaliwal, Navroop K.; Miri, Kamelia; Davidson, Scott; Jarkass, Hala Tamim El; Mitchell, Jennifer A.

doi:10.1016/j.stemcr.2018.02.007

Cited by 44 publications

(58 citation statements)

References 33 publications

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“…Although KLF4 restores loss of stemness caused by deletion of Klf5 in murine ESCs , the fact that Klf4‐ null embryos can develop to term suggests either that KLF4 is dispensable for embryogenesis or there is a functional compensation by other KLF proteins . KLF4 and NANOG are among the first transcription factors to shut down their transcription when ESCs exit pluripotency, and nuclear export of KLF4 upon ERK activation is a critical first step to exit the naive pluripotent state and initiate ESC differentiation . In addition, KLF4 is required for expression of the telomerase reverse transcriptase (TERT) in human ESCs and binds β‐catenin through protein‐to‐protein interaction, allowing the recruitment of this dimer to the Tert promoter in murine ESCs .…”

Section: Regulation Of Self‐renewal By Klfs In Pluripotent Stem Cellsmentioning

confidence: 99%

Concise Review: Regulation of Self-Renewal in Normal and Malignant Hematopoietic Stem Cells by Krüppel-Like Factor 4

Park

Lewis

Chen

et al. 2019

Stem Cells Translational Medicine

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Pluripotent and tissue‐specific stem cells, such as blood‐forming stem cells, are maintained through a balance of quiescence, self‐renewal, and differentiation. Self‐renewal is a specialized cell division that generates daughter cells with the same features as the parental stem cell. Although many factors are involved in the regulation of self‐renewal, perhaps the most well‐known factors are members of the Krüppel‐like factor (KLF) family, especially KLF4, because of the landmark discovery that this protein is required to reprogram somatic cells into induced pluripotent stem cells. Because KLF4 regulates gene expression through transcriptional activation or repression via either DNA binding or protein‐to‐protein interactions, the outcome of KLF4‐mediated regulation largely depends on the cellular context, cell cycle regulation, chromatin structure, and the presence of oncogenic drivers. This study first summarizes the current understanding of the regulation of self‐renewal by KLF proteins in embryonic stem cells through a KLF circuitry and then delves into the potential function of KLF4 in normal hematopoietic stem cells and its emerging role in leukemia‐initiating cells from pediatric patients with T‐cell acute lymphoblastic leukemia via repression of the mitogen‐activated protein kinase 7 pathway. stem cells translational medicine 2019;8:568–574

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Section: Regulation Of Self‐renewal By Klfs In Pluripotent Stem Cellsmentioning

confidence: 99%

Concise Review: Regulation of Self-Renewal in Normal and Malignant Hematopoietic Stem Cells by Krüppel-Like Factor 4

Park

Lewis

Chen

et al. 2019

Stem Cells Translational Medicine

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“…For ES cells maintained in LIF/serum, KLF4 displayed low protein stability similar to the observed stability after removal of MEKi ( Figure S2). Previous studies demonstrated that these signaling pathways regulate gene transcription (Dhaliwal et al, 2018;Nichols and Smith, 2009;Theunissen et al, 2011;Zhang et al, 2010); therefore, we investigated the effect of individual signaling pathways on Klf4, Nanog, Oct4, Sox2, Klf2 and Klf5 transcription. We observed that the removal of MEKi alone or in combination with LIF/GSK3i for 12hr significantly reduces Klf4 and Nanog transcription, but Oct4, Sox2, Klf2 and Klf5 transcription remains unaffected ( Figure S3).…”

Section: Klf4 Protein Stability Is Regulated By Lif and Mapk Signalinmentioning

confidence: 99%

“…The MAPK pathway has been shown to have a role in KLF4 nuclear localization, ubiquitination and degradation (Dhaliwal et al, 2018;Kim et al, 2012;Kim et al, 2014). As early as 6hr after MEKi removal, KLF4 was observed to exit the nucleus, and cytoplasmic KLF4 undergoes proteosomal degradation (Dhaliwal et al, 2018). In addition, nuclear export was found to depend on the presence of both a KLF4 nuclear export signal (NES1 at 97-107) and the ERK phosphorylation site in KLF4 at S132 (Dhaliwal et al, 2018).…”

Section: Klf4 Protein Stability Is Regulated By Lif and Mapk Signalinmentioning

confidence: 99%

“…Differentiation of embryonic stem (ES) cells requires disruption to the regulatory network that maintains pluripotency gene expression. Kruppel-like factor 4 (KLF4), a member of the Kruppellike factor family of conserved zinc finger transcription factors, is known to interact with the core network of pluripotency transcription factors (NANOG,SOX2 and OCT4) in order to regulate genes required for maintenance of pluripotency and reprogramming (Dhaliwal et al, 2018;Wei et al, 2013;Wei et al, 2009;Xie et al, 2017;Zhang et al, 2010). Sustained expression of constitutively nuclear KLF4 prevents differentiation of ES cells indicating that a loss of KLF4 protein function is required for differentiation (Dhaliwal et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Kruppel-like factor 4 (KLF4), a member of the Kruppellike factor family of conserved zinc finger transcription factors, is known to interact with the core network of pluripotency transcription factors (NANOG,SOX2 and OCT4) in order to regulate genes required for maintenance of pluripotency and reprogramming (Dhaliwal et al, 2018;Wei et al, 2013;Wei et al, 2009;Xie et al, 2017;Zhang et al, 2010). Sustained expression of constitutively nuclear KLF4 prevents differentiation of ES cells indicating that a loss of KLF4 protein function is required for differentiation (Dhaliwal et al, 2018). It is generally accepted that differentiation occurs due to a loss of pluripotency transcription factor activity at enhancers which disrupts pluripotency gene expression and allows for the expression of differentiation associated genes; however, the molecular mechanisms through which this disruption occurs are not well defined.…”

Section: Introductionmentioning

confidence: 99%

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KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control

Dhaliwal

Abatti

Mitchell

2019

Preprint

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Embryonic stem (ES) cells are regulated by a network of transcription factors which maintain the pluripotent state. Differentiation relies on downregulation of pluripotency transcription factors disrupting this network. While investigating transcriptional regulation of the pluripotency transcription factor Klf4, we observed homozygous deletion of distal enhancers caused 17 fold decrease in Klf4 transcript but surprisingly decreased protein levels by less than 2 fold indicating post-transcriptional control of KLF4 protein overrides transcriptional control. The lack of sensitivity of KLF4 to transcription is due to high protein stability (half-life >24hr). This stability is context dependent and disrupted during differentiation, evidenced by a shift to a half-life of <2hr. KLF4 protein stability is maintained through interaction with other pluripotency transcription factors (NANOG, SOX2 and STAT3) that together facilitate association of KLF4 with RNA polymerase II. In addition, the KLF4 DNA binding and transactivation domains are required for optimal KLF4 protein stability. Post-translational modification of KLF4 destabilizes the protein as cells exit the pluripotent state and mutations that prevent this destabilization also prevent differentiation. These data indicate the core pluripotency transcription factors are integrated by post-translational mechanisms to maintain the pluripotent state, and identify mutations that increase KLF4 protein stability while maintaining transcription factor function.

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Identification of calmodulin‐like protein 5 as tumor‐suppressor gene silenced during early stage of carcinogenesis in squamous cell carcinoma of uterine cervix

Kitazawa

Takaoka

Ueda

et al. 2021

Intl Journal of Cancer

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In the course of identifying the molecular mechanism that is related to strong cell-cell adhesion in stratified structures of the squamous epithelium, calmodulin-like protein 5 (CALML5) was identified as a spinous structure-associated protein by producing monoclonal antibodies with the use of the crude intercellular portion of squamous tissue as an immunogen and by subsequent morphologic screening. By electrophoretic mobility shift assay (EMSA) and a series of mutagenesis studies, two transcription factors, ZNF750 and KLF4, by binding in line to the CALML5 gene promoter, were found to play a central role in CALML5 transcription. Knockdown of CALML5 by siRNA in the A431 cell line that expresses high levels of CALML5 resulted in the acceleration of wound confluence in a scratch assay, indicating that CALML5 functions as a tumor-suppressor in uterine cervical cancer. Immunohistochemical evaluation of squamous intraepithelial lesions, carcinoma in situ (CIS) and invasive uterine cancer, revealed a reduction in CALML5 expression during the stages of CIS through various molecular pathways including the blockage of the nuclear translocation of KLF4. Conversely, restoration of the nuclear translocation of KLF4 by inhibiting ERK-signaling reactivated CALML5 expression in ME180 cells expressing low levels of CALML5. Thus, alteration of the p63-ZNF750-KLF4 axis may result in critical functional loss of CALM-related genes during cancer progression.Although the morphological association of CALML5 with the spiny-structure in relation to cell motility is not clear, evaluation of CALML5 expression provides a useful diagnostic indicator of differentiating dysplasia, preinvasive and invasive cervical cancers.

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KLF4 Nuclear Export Requires ERK Activation and Initiates Exit from Naive Pluripotency

Cited by 44 publications

References 33 publications

Concise Review: Regulation of Self-Renewal in Normal and Malignant Hematopoietic Stem Cells by Krüppel-Like Factor 4

Concise Review: Regulation of Self-Renewal in Normal and Malignant Hematopoietic Stem Cells by Krüppel-Like Factor 4

KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control

Identification of calmodulin‐like protein 5 as tumor‐suppressor gene silenced during early stage of carcinogenesis in squamous cell carcinoma of uterine cervix

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