Histone Acetyl Transferase (HAT) HBO1 and JADE1 in Epithelial Cell Regeneration

Properly controlled intestinal epithelial cell regeneration is not only vital for protection against insults from environmental hazards but also crucial for preventing intestinal cancer. Intestinal stem cells located in the crypt region provide the driving force for epithelial regeneration, and thus their survival and death must be precisely regulated. We show here that polypyrimidine tract binding protein 1 (PTBP1, also called heterogeneous nuclear ribonucleoprotein I, or HNRNP I), an RNA-binding protein that post-transcriptionally regulates gene expression, is critical for intestinal stem cell survival and stemness. Mechanistically, we show that PTBP1 inhibits the expression of PHLDA3, an AKT repressor, and thereby maintains AKT activity in the intestinal stem cell compartment to promote stem cell survival and proliferation. Furthermore, we show that PTBP1 inhibits the expression of PTBP2, a paralog of PTBP1 that is known to induce neuron differentiation, through repressing inclusion of alternative exon 10 to Ptbp2 transcript. Loss of PTBP1 results in a significant upregulation of PTBP2, which is accompanied by splicing changes in genes that are important for neuron cell development. This finding suggests that PTBP1 prevents aberrant differentiation of intestinal stem cells into neuronal cells through inhibiting PTBP2. Our results thus reveal a novel mechanism whereby PTBP1 maintains intestinal stem cell survival and stemness through the control of gene function post-transcriptionally.

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Essential Role of mTOR Signaling in Human Retinal Pigment Epithelial Cell Regeneration After Laser Photocoagulation

Lasers in Medical Science ◽

10.1007/s10103-018-2692-5 ◽

2018 ◽

Vol 34 (5) ◽

pp. 1019-1029

Author(s):

Sanjar Batirovich Madrakhimov ◽

Jin Young Yang ◽

Ha Yan Park ◽

Tae Kwann Park

Keyword(s):

Epithelial Cell ◽

Laser Photocoagulation ◽

Essential Role ◽

Retinal Pigment Epithelial ◽

Retinal Pigment Epithelial Cell ◽

Retinal Pigment ◽

Mtor Signaling ◽

Cell Regeneration ◽

Pigment Epithelial

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Cadmium-Induced Renal Damage and Proinflammatory Cytokines: Possible Role of IL-6 in Tubular Epithelial Cell Regeneration

Toxicology and Applied Pharmacology ◽

10.1006/taap.1995.1165 ◽

1995 ◽

Vol 134 (1) ◽

pp. 26-34 ◽

Cited By ~ 50

Author(s):

F. Kayama ◽

T. Yoshida ◽

M.R. Elwell ◽

M.I. Luster

Keyword(s):

Epithelial Cell ◽

Proinflammatory Cytokines ◽

Renal Damage ◽

Tubular Epithelial Cell ◽

Cell Regeneration

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CD74 Signaling Links Inflammation to Intestinal Epithelial Cell Regeneration and Promotes Mucosal Healing

Cellular and Molecular Gastroenterology and Hepatology ◽

10.1016/j.jcmgh.2020.01.009 ◽

2020 ◽

Vol 10 (1) ◽

pp. 101-112 ◽

Cited By ~ 2

Author(s):

Laura Farr ◽

Swagata Ghosh ◽

Nona Jiang ◽

Koji Watanabe ◽

Mahmut Parlak ◽

...

Keyword(s):

Epithelial Cell ◽

Intestinal Epithelial Cell ◽

Mucosal Healing ◽

Cell Regeneration ◽

Intestinal Epithelial

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Ablation of Gsa impairs renal tubule proliferation after injury via CDK2/cyclin E

AJP Renal Physiology ◽

10.1152/ajprenal.00367.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. F793-F803 ◽

Cited By ~ 1

Author(s):

Lele Liu ◽

Yuanjun Deng ◽

Yang Cai ◽

Pingfan Lu ◽

Yiyan Guo ◽

...

Keyword(s):

Epithelial Cell ◽

Renal Tubule ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Cell Regeneration ◽

Cyclin Dependent Kinase ◽

Renal Tubular Epithelial Cell ◽

Cyclin E1 ◽

Renal Tubular

Acute kidney injury has a high global morbidity associated with an increased risk of death and chronic kidney disease. Renal tubular epithelial cell regeneration following injury may be a decisive factor in renal repair or the progression of acute kidney injury to chronic kidney disease, but the underlying mechanism of abnormal renal tubular repair remains unclear. In the present study, we investigated the role of heterotrimeric G stimulatory protein α-subunit (Gsa) in renal tubular epithelial cell regeneration. We generated renal tubule epithelium-specific Gsa knockout (GsaKspKO) mice to show the essential role of Gsa in renal tubular epithelial cell regeneration in two AKI models: acute aristolochic acid nephropathy (AAN) and unilateral ischemia-reperfusion injury (UIRI). GsaKspKO mice developed more severe renal impairment after AAN and UIRI, higher serum creatinine levels, and more substantial tubular necrosis than wild-type mice. More importantly, Gsa inactivation impaired renal tubular epithelial cell proliferation by reducing bromodeoxyuridine+ cell numbers in the AAN model and inhibiting cyclin-dependent kinase 2/cyclin E1 expression in the UIRI model. This reduced proliferation was further supported in vitro with Gsa-targeting siRNA. Downregulation of Gsa inhibited tubular epithelial cell proliferation in HK-2 and mIMCD-3 cells. Furthermore, Gsa downregulation inhibited cyclin-dependent kinase 2/cyclin E1 expression, which was dependent on the Raf-MEK-ERK signaling pathway. In conclusion, Gsa is required for tubular epithelial cell regeneration during kidney repair after AKI. Loss of Gsa impairs renal tubular epithelial cell regeneration by blocking the Raf-MEK-ERK pathway.

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Mechanism of Villous Atrophy in Celiac Disease: Role of Apoptosis and Epithelial Regeneration

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2012-0354-oa ◽

2013 ◽

Vol 137 (9) ◽

pp. 1262-1269 ◽

Cited By ~ 27

Author(s):

DM Shalimar ◽

Prasenjit Das ◽

Vishnubhatla Sreenivas ◽

Siddhartha Datta Gupta ◽

Subrat K. Panda ◽

...

Keyword(s):

Celiac Disease ◽

Epithelial Cell ◽

Villous Atrophy ◽

Proliferation Index ◽

Cell Regeneration ◽

Ki 67 ◽

Epithelial Regeneration ◽

Treatment Naïve ◽

Apoptotic Pathways

Context.—The data on status of apoptosis in patients with celiac disease are conflicting. Furthermore, complex interaction between intrinsic and common apoptotic pathways, apoptotic inhibitors, and epithelial cell proliferation is largely unclear for patients with celiac disease. Objectives.—To determine the role of apoptosis and epithelial cell regeneration in celiac disease. Design.—Twenty-five treatment-naïve patients with celiac disease and 6 patients with functional dyspepsia, as controls, were included and duodenal biopsy specimens from all were subjected to immunohistochemistry with markers of intrinsic apoptotic pathway (AIF, H2AX, p53), common pathway (CC3, M30), apoptotic inhibitors (XIAP, Bcl2), and epithelial proliferation (Ki-67). Apoptotic and proliferation indices were calculated. Results.—Expression of end-apoptotic products, that is, H2AX in the cell nuclei (P = .01) and M30 in the cell cytoplasm (P < .01), was significantly upregulated in celiac disease in comparison to controls. Cleaved caspase-3 was also upregulated in villous cytoplasm in celiac disease. Apoptotic inhibitor Bcl2 was significantly down-regulated in celiac disease in comparison to controls. In addition, Ki-67 proliferation index was upregulated both in the crypts and villous mucosal epithelium in comparison to the crypts of the controls. Conclusions.—Treatment-naïve patients with celiac disease have significantly higher level of apoptosis that involves both the common and intrinsic apoptotic pathways. Increased apoptosis and unequaled cell regeneration in crypts probably results in villous atrophy. Down-regulation of apoptotic inhibitors in treatment-naïve celiac disease imparts an additional pro-apoptotic effect.

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