Mitogen-activated protein kinase (MAPK) pathways are activated by several stimuli and transduce the signal inside cells, generating diverse responses including cell proliferation, differentiation, ...migration and apoptosis. Each MAPK cascade comprises a series of molecules, and regulation takes place at different levels. They communicate with each other and with additional pathways, creating a signaling network that is important for cell fate determination. In this review, we focus on ERK, JNK, p38 and ERK5, the major MAPKs, and their interactions with PI3K-Akt, TGFβ/Smad and Wnt/β-catenin pathways. More importantly, we describe how MAPKs regulate cell proliferation and differentiation in the rapidly renewing epithelia that lines the gastrointestinal tract and, finally, we highlight the recent findings on nutritional aspects that affect MAPK transduction cascades.
The gastric mucosa is disturbed when breastfeeding is interrupted, and such early weaning (EW) condition permanently affects the differentiation of zymogenic cells. The aim of the study was to ...evaluate the immediate and long-term effects of EW on gastric cell proliferation, considering the molecular markers for cell cycle, inflammation, and metaplasia. Overall, we investigated the lifelong adaptation of gastric growth. Wistar rats were divided into suckling-control (S) and EW groups, and gastric samples were collected at 18, 30, and 60 days for morphology, RNA, and protein isolation. Inflammation and metaplasia were not identified, but we observed that EW promptly increased Ki-67-proliferative index (PI) and mucosa thickness (18 days). From 18 to 30 days, PI increased in S rats, whereas it was stable in EW animals, and such developmental change in S made its PI higher than in EW. At 60 days, the PI decreased in S, making the indices similar between groups. Spatially, during development, proliferative cells spread along the gland, whereas, in adults, they concentrate at the isthmus-neck area. EW pushed dividing cells to this compartment (18 days), increased PI at the gland base (60 days), but it did not interfere in expression of cell cycle molecules. At 18 days, EW reduced
Tgfβ2
,
Tgfβ3
, and
Tgfbr2
and TβRII and p27 levels, which might regulate the proliferative increase at this age. We demonstrated that gastric cell proliferation is immediately upregulated by EW, corroborating previous results, but for the first time, we showed that such increased PI is stable during growth and aging. We suggest that suckling and early weaning might use TGFβs and p27 to trigger different proliferative profiles during life course.
Paneth cells and their multiple functions Barreto e Barreto, Laylla; Rattes, Isadora C.; Costa, Aline V. ...
Cell biology international,
20/May , Letnik:
46, Številka:
5
Journal Article
Recenzirano
The small intestine mucosa is lined by specialized cells that form the crypt‐villus axis, which expands its surface. Among the six intestinal epithelial cell types, the Paneth cell is located at the ...base of the crypt, and it contains numerous granules in its cytoplasm, composed of antimicrobial peptides, such as defensins and lysozyme, and growth factors, such as epidermal growth factor, transforming growth factor‐α, and Wnt ligands. Together, these elements act in the defense against microorganisms, regulation of intestinal microbiota, maintenance, and regulation of stem cell identity. Pathologies that target Paneth cells can disturb such defense activity, but they also affect the maintenance of the stem cell niche. In that way, Crohn's disease, necrotizing enterocolitis, and graft‐versus‐host disease promote a reduction of Paneth cell population, and, consequently, secretion of their products into the lumen of the crypts, making the affected organism predisposed to infections and dysbiosis. Additionally, the emergence of new intestinal cells is also decreased. This review aims to address the main characteristics of Paneth cells, highlighting their multiple functions and the importance of their preservation to ensure bowel homeostasis.
During postnatal development, colostrum and breastmilk are sequentially the first sources of nutrition with protein components and bioactive molecules that confer protection and immunostimulatory ...function to the gut. Caseins, whey proteins, secretory immunoglobulin A (sIgA), mucins, tryptophan, and growth factors are among milk‐borne elements that are directly important in the control of mucosa development and protection. Consequently, breastfeeding is associated with the low incidence of gastrointestinal inflammation and with the decrease in respiratory diseases during postnatal period. The novel coronavirus (SARS‐CoV‐2) binds to angiotensin II‐converting enzyme (ACE2) on the cell membrane, allowing virus entrance, replication, and host commitment. ACE2 is expressed by different cell types, which include ciliated cells in the lungs and enterocytes in the intestine. Such cells are highly active in metabolism, as they internalize molecules to be processed and used by the organism. The disruption of ACE2 impairs leads to intestinal inflammation and decreased synthesis of serotonin, affecting motility. By reviewing the effects of SARS‐CoV‐2 in the gastrointestinal and respiratory tracts in infants, and gut responses to breastfeeding interruption, we suggest that it is important to maintain breastfeeding during SARS‐CoV‐2 infection, as it might be essential to protect newborns from gastrointestinal‐associated disorders and relieve disease symptoms.
We currently reviewed the effects of SARS‐CoV‐2 in the gastrointestinal and respiratory tracts in infants and discussed gut responses to breastfeeding interruption, and we suggest that it is important to maintain breastfeeding during SARS‐CoV‐2 infection, as it might be essential to protect newborns from gastrointestinal‐associated disorders and relieve disease symptoms.
Neonatal- Maternal Separation (NMS) deprives mammals from breastfeeding and maternal care, influencing growth during suckling- weaning transition. In the gastric mucosa, Mist1 (encoded by Bhlha15 ...gene) and moesin organize the secretory apparatus for pepsinogen C in zymogenic cells. Our current hypothesis was that NMS would change corticosterone activity through receptors (GR), which would modify molecules involved in zymogenic cell differentiation in rats. We found that NMS increased corticosterone levels from 18 days onwards, as GR decreased in the gastric mucosa. However, as nuclear GR was detected, we investigated receptor binding to responsive elements (GRE) and observed an augment in NMS groups. Next, we demonstrated that NMS increased zymogenic population (18 and and 30 days), and targeted Mist1 and moesin. Finally, we searched for evolutionarily conserved sequences that contained GRE in genes involved in pepsinogen C secretion, and found that the genomic regions of Bhlha15 and PgC contained sites highly likely to be responsive to glucocorticoids. We suggest that NMS triggers GR- GRE to enhance the expression and to prime genes that organize cellular architecture in zymogenic population for PgC function. As pepsinogen C- pepsin is essential for digestion, disturbance of parenting through NMS might alter functions of gastric mucosa in a permanent manner.
During rat postnatal development, gastric cell proliferation and differentiation depend on many elements, which include dietary pattern, hormones, growth factors and their signaling pathways. Among ...them, EGFR activity is increased through MAPK and Src cascades in response to early weaning that represents the abrupt transition from milk to solid food. We herein investigated the direct involvement of ERK pathway in the control of cell cycle progression during early weaning, and studied the specific role of p27. At 15 days, Wistar rats were separated from dams, fed with powdered chow and daily injected with PD98059 (MEK inhibitor, 300 µg/kg) or 0.5% DMSO (control). By using HE staining and immunohistochemistry for PCNA, we respectively detected mitotic (MI) and proliferative (PI) indices in 18-day-old pups, and observed that both were reduced by PD98059. As cell cycle-related proteins (cyclin E, CDK2, cyclin D1, CDK4, p21 and p27) are involved in proliferative regulation, we compared samples obtained at 17 days in the morning (17 d) and evening (17.5 d). We found that they were not altered after ERK inhibition, but cyclin D1, p21 and p27 levels changed throughout the day in the control group. As p27 activity depends on its integrity, we studied p27 phosphorylation (threonin 187), and observed that ERK inhibition reduced this process. We suggest that MAPK pathway interferes in the regulation of p27 function in the gastric mucosa during early weaning, possibly by controlling its degradation, and altogether this mechanism might contribute to the increase of epithelial proliferation at this condition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
We discovered that pigment epithelium-derived factor (PEDF)–null mice have endometrial hyperplasia, the precursor to human type I endometrial cancer (ECA), which is etiologically linked to ...unopposed estrogen (E2), suggesting that this potent antiangiogenic factor might contribute to dysregulated growth and the development of type I ECA. Treatment of both ECA cell lines and primary ECA cells with recombinant PEDF dose dependently decreased cellular proliferation via an autocrine mechanism by blocking cells in G1 and G2 phases of the cell cycle. Consistent with the known opposing effects of E2 and progesterone (Pg) on endometrial proliferation, Pg increases PEDF protein synthesis and release, whereas E2 has the converse effect. Using PEDF luciferase promoter constructs containing two Pg and one E2 response elements, E2 reduced and Pg increased promoter activity due to distal response elements. Furthermore, E2 decreases and Pg increases PEDF secretion into conditioned media (CM) by both normal endometrial stromal fibroblasts (ESFs) and cancer-associated fibroblasts (CAFs), but only CM from ESFs mediated growth-inhibitory activity of primary endometrial epithelial cells (EECs). In addition, in cocultures with primary EECs, Pg-induced growth inhibition is mediated by ESFs, but not CAFs. This is consistent with reduced levels of Pg receptors on CAFs surrounding human malignant glands in vivo. Taken together, the data suggest that PEDF is a hormone-regulated negative autocrine mediator of endometrial proliferation, and that paracrine growth inhibition by soluble factors, possibly PEDF, released by ESFs in response to Pg, but not CAFs, exemplifies a tumor microenvironment that contributes to the pathogenesis of ECA.
PEDF is an estrogen and progesterone hormone–regulated autocrine mediator of primary endometrial cancer (ECA) cells and ECA cell line proliferation but is not a biomarker for ECA.
: Gastric glands grow and cells reach differentiation at weaning in rats. By considering that early weaning (EW) can affect the timing of development, we aimed to compare molecular and cellular ...markers of differentiation in pups and adults.
: Wistar rats were separated into suckling-control (S) and EW groups at 15 days. Stomachs were collected at 15, 18, and 60 days for RNA and protein extraction, and morphology.
: After EW, the expression of genes involved in differentiation (
,
and
) augmented (18 days), and
and
were high at 60 days. EW increased the number of zymogenic cells (ZC) in pups and adults and augmented mucous neck cells only at 18 days, whereas parietal and transition cells (TC) were unchanged.
: EW affected the gastric mucosa mostly in a transient manner as the changes in gene expression and distribution of differentiated cells that were detected in pups were not fully maintained in adults, except for the size of ZC population. We concluded that though most of EW effects were immediate, such nutritional change in the infancy might affect part of gastric digestive functions in a permanent manner, as some markers were kept unbalanced in the adulthood.
Throughout postnatal development, the gastric epithelium expresses Transforming Growth Factor beta1 (TGFβ1), but it is also exposed to luminal peptides that are part of milk. During suckling period, ...fasting promotes the withdrawal of milk-born molecules while it stimulates gastric epithelial cell proliferation. Such response can be reversed by exogenous TGFβ1, as it directly affects cell cycle through the regulation of p27 levels. We used fasting condition to induce the hyperproliferation of gastric epithelial cells in 14-day-old Wistar rats, and evaluated the effects of TGFβ1 gavage on p27 expression, phosphorylation at threonine 187 (phospho-p27Thr187) and degradation. p27 protein level was reduced during fasting when compared to suckling counterparts, while phospho-p27Thr187/p27 ratio was increased. TGFβ1 gavage reversed this response, which was confirmed through immunostaining. By using a neutralizing antibody against TGFβ1, we found that it restored the p27 and phosphorylation levels detected during fasting, indicating the specific role of the growth factor. We noted that neither fasting nor TGFβ1 changed p27 expression, but after cycloheximide administration, we observed that protein synthesis was influenced by TGFβ1. Next, we evaluated the capacity of the gastric mucosa to degrade p27 and we recorded a higher concentration of the remaining protein in pups treated with TGFβ1, suggesting augmented stability under this condition. Thus, we showed for the first time that luminal TGFβ1 increased p27 levels in the rat gastric mucosa by up- regulating translation and reducing protein degradation. We concluded that such mechanisms might be used by rapidly proliferating cells to respond to milk-born TGFβ1 and food restriction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Germline mutations in p27kip1 are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms ...of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.01), particularly for those with ACTH-secreting pituitary adenomas (P=0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.
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