Intestinal Cell Proliferation and Senescence Are Regulated by Receptor Guanylyl Cyclase C and p21

Basu, Nirmalya; Saha, Sayanti; Khan, Imran A.; Ramachandra, Subbaraya G.; Visweswariah, Sandhya S.

doi:10.1074/jbc.m113.511311

Cited by 53 publications

(44 citation statements)

References 66 publications

(67 reference statements)

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“…Next, flow cytometric analysis revealed that downregulation of FALEC might contribute to the cell arrest in G1/G0 phase of cell cycle. P21 are family members of cyclin‐dependent kinase inhibitors, which is responsible for arresting cells in G1 phases and negatively control cell proliferation, acting as tumor suppressor . In the present study, cells with down regulation of FALEC leads to increased level of p21 and relative change of downstream CKI and cyclin, indicating that FALEC exerts its oncogenic function at least in part via suppressing of p21 expression.…”

Section: Discussionsupporting

confidence: 51%

Upregulation of the long non‐coding RNA FALEC promotes proliferation and migration of prostate cancer cell lines and predicts prognosis of PCa patients

et al. 2017

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Section: Discussionsupporting

confidence: 51%

Upregulation of the long non‐coding RNA FALEC promotes proliferation and migration of prostate cancer cell lines and predicts prognosis of PCa patients

et al. 2017

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“…Further, GUCY2C signaling regulates proliferation and DNA damage repair, processes that are canonically disrupted in RIGS (26). Indeed, signaling through the GUCY2C-cGMP axis inhibits DNA synthesis and prolongs the cell cycle, imposing a G1-S delay in part by regulating p21, key injury responses to radiation (18–20,50). Further, silencing GUCY2C increases DNA oxidation and double strand breaks, amplifying mutations induced by chemical or genetic DNA damage, reflecting ROS and inadequate repair (20).…”

Section: Discussionmentioning

confidence: 99%

GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome

et al. 2017

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High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation and intestinal dysfunction. Durable expression of GUCY2C, guanylin and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess™; Trulance™) to prevent and treat RIGS in cancer therapy and nuclear disasters.

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“…GUCY2C-deficient (Gucy2c 2/2 ) mice exhibit epithelial dysfunction that recapitulates discreet attributes of tumorigenesis, including an expanded proliferating crypt compartment, increased DNA damage, metabolic reprogramming to a Warburg glycolytic phenotype, restricted differentiation and lineage commitment, and amplified oncogenic signaling through changes in p21, Akt, and other pathways (Li et al, 2007b;Rinaldi et al, 2010;Han et al, 2011;Okabayashi et al, 2012). Consistent with its role as a tumor suppressor, intestinal neoplasia in Gucy2c 2/2 mice was substantially increased, compared with wild-type mice, by the chemical carcinogen azoxymethane or by mutations in adenomatous polyposis coli (Li et al, 2007b;Rinaldi et al, 2010;Basu et al, 2014).…”

Section: Gucy2c Signaling and The Paracrine Hormone Hypothesis Of Colmentioning

confidence: 50%

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

et al. 2016

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Obesity has emerged as a principal cause of mortality worldwide, reflecting comorbidities including cancer risk, particularly in colorectum. Although this relationship is established epidemiologically, molecular mechanisms linking colorectal cancer and obesity continue to be refined. Guanylyl cyclase C (GUCY2C), a membrane-bound guanylyl cyclase expressed in intestinal epithelial cells, binds the paracrine hormones guanylin and uroguanylin, inducing cGMP signaling in colorectum and small intestine, respectively. Guanylin is the most commonly lost gene product in sporadic colorectal cancer, and its universal loss early in transformation silences GUCY2C, a tumor suppressor, disrupting epithelial homeostasis underlying tumorigenesis. In small intestine, eating induces endocrine secretion of uroguanylin, the afferent limb of a novel gut-brain axis that activates hypothalamic GUCY2C-cGMP signaling mediating satiety opposing obesity. Recent studies revealed that dietinduced obesity suppressed guanylin and uroguanylin expression in mice and humans. Hormone loss reflects reversible calorieinduced endoplasmic reticulum stress and the associated unfolded protein response, rather than the endocrine, adipokine, or inflammatory milieu of obesity. Loss of intestinal uroguanylin secretion silences the hypothalamic GUCY2C endocrine axis, creating a feed-forward loop contributing to hyperphagia in obesity. Importantly, calorie-induced guanylin loss silences the GUCY2C-cGMP paracrine axis underlying obesity-induced epithelial dysfunction and colorectal tumorigenesis. Indeed, genetically enforced guanylin replacement eliminated diet-induced intestinal tumorigenesis in mice. Taken together, these observations suggest that GUCY2C hormone axes are at the intersection of obesity and colorectal cancer. Moreover, they suggest that hormone replacement that restores GUCY2C signaling may be a novel therapeutic paradigm to prevent both hyperphagia and intestinal tumorigenesis in obesity.

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Intestinal Cell Proliferation and Senescence Are Regulated by Receptor Guanylyl Cyclase C and p21

Cited by 53 publications

References 66 publications

Upregulation of the long non‐coding RNA FALEC promotes proliferation and migration of prostate cancer cell lines and predicts prognosis of PCa patients

Upregulation of the long non‐coding RNA FALEC promotes proliferation and migration of prostate cancer cell lines and predicts prognosis of PCa patients

GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

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