A critical role for the protein kinase PKK in the maintenance of recirculating mature B cells and the development of B1 cells

Chen, Luojing; Oleksyn, David; Pulvino, Mary; Sanz, Igñacio; Ryan, Daniel; Ryan, Charlotte; Lin, Chyuan‐Sheng; Poligone, Brian; Pentland, Alice P.; Ritchlin, Christopher T.; Zhao, Jiapeng

doi:10.1016/j.imlet.2016.02.015

Cited by 6 publications

(24 citation statements)

References 55 publications

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“…Sle1.Sle3 [20, 26, 35] and the B-cell specific PKK conditional knockout mice PKK f/f CD19-Cre [30] were previously described. These mice were utilized to generate mice that carried the Sle1 and Sle3 loci with PKK deletion in B cells (Sle1.Sle3.…”

Section: Methodsmentioning

confidence: 99%

“…The presence of the four alleles ( Sle1 , Sle3 , PKK f/f and CD19-Cre) was confirmed by PCR using the specific primers as previously described [26, 30, 36]. Ablation of the PKK in spleen B cells was confirmed by PCR as previously described [30]. The mice described in this study were all heterozygous for CD19-Cre (CD19-Cre +/− ) so that one functional CD19 allele, which is required for B cell development, was maintained.…”

Section: Methodsmentioning

confidence: 99%

“…Single-cell suspensions were prepared from the indicated tissues, and subsets of B cells and T cells were identified using a combination of antibodies as previously described [30, 40, 41]. All antibodies used in the experiments described here were from BD Biosciences.…”

Section: Methodsmentioning

confidence: 99%

“…The cells were stained with anti-B220 antibody, and the apoptotic B cells (B220 + gated cells) were assayed using the Annexin V apoptosis detection kit (BD Bioscience) as previously described [30, 34]. …”

Section: Methodsmentioning

confidence: 99%

“…Employing B cell-specific PKK conditional knockout mice, we recently demonstrated that PKK is required for the development of B1 cells and the maintenance of long-lived recirculating mature B cells through, at least in part, the regulation of BCR-mediated NF-κB activation [30]. Consistent with its role in the maintenance of active B cells, PKK was also shown to be required for the proliferation and survival of diffuse large B cell lymphoma cells in our previous studies [34].…”

Section: Introductionmentioning

confidence: 99%

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PKK deficiency in B cells prevents lupus development in Sle lupus mice

et al. 2017

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B- lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PKK deficiency in B cells prevents lupus development in Sle lupus mice

et al. 2017

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PKK deletion in basal keratinocytes promotes tumorigenesis after chemical carcinogenesis

Chen

Hayden

Gilmore³

et al. 2017

Carcinogenesis

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Squamous cell carcinoma (SCC) of the skin is a keratinocyte malignancy characterized by tumors presenting on sun-exposed areas with surgery being the mainstay treatment. Despite advances in targeted therapy in other skin cancers, such as basal cell carcinoma and melanoma, there have been no such advances in the treatment of SCC. This is partly due to an incomplete knowledge of the pathogenesis of SCC. We have recently identified a protein kinase C-associated kinase (PKK) as a potential tumor suppressor in SCC. We now describe a novel conditional PKK knockout mouse model, which demonstrates that PKK deficiency promotes SCC formation during chemically induced tumorigenesis. Our results further support that PKK functions as a tumor suppressor in skin keratinocytes and is important in the pathogenesis of SCC of the skin. We further define the interactions of keratinocyte PKK with TP63 and NF-κB signaling, highlighting the importance of this protein as a tumor suppressor in SCC development.

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Lysophosphatidic acid down-regulates human RIPK4 mRNA in keratinocyte- derived cell lines

Xu,

Bajorski,

Poligone

2024

PLoS ONE

Self Cite

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The tight control of proliferating keratinocytes is vital to the successful function of the skin. Differentiation of dividing cells is necessary to form a skin barrier. The same dividing cells are necessary to heal wounds and when malignant form tumors. RIPK4, a serine-threonine kinase, plays critical roles in these processes. Its loss of function was associated with pathological keratinocyte proliferation and development of squamous cell carcinoma (SCC) in humans and mice. The current study extends previous findings in the importance of RIPK4 in keratinocyte proliferation. A serum-derived phospholipid, lysophosphatidic acid (LPA), was identified as an important biologic inhibitor of RIPK4. LPA functions by inhibiting the transcription of RIPK4 mRNA. LPA treatment led to increased keratinocyte proliferation, and this was compromised in cells with reduced RIPK4 expression. The current study may help to explain the mechanism by which RIPK4 was downregulated during SCC progression and provide insights on RIPK4 functions. It may also allow for targeting of RIPK4 through a natural component of serum.

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A critical role for the protein kinase PKK in the maintenance of recirculating mature B cells and the development of B1 cells

Cited by 6 publications

References 55 publications

PKK deficiency in B cells prevents lupus development in Sle lupus mice

PKK deficiency in B cells prevents lupus development in Sle lupus mice

PKK deletion in basal keratinocytes promotes tumorigenesis after chemical carcinogenesis

Lysophosphatidic acid down-regulates human RIPK4 mRNA in keratinocyte- derived cell lines

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