Aging is associated with increased proliferation and decreased apoptosis in the colonic mucosa

Xiao, Zhousheng; Moragoda, Lathika; Jaszewski, Richard; Hatfield, James; Fligiel, Suzanne E. G.; Majumdar, Adhip P.N.

doi:10.1016/s0047-6374(01)00323-2

Cited by 71 publications

(36 citation statements)

References 29 publications

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“…Because normal tissue homeostasis requires the physiological deletion of cells by apoptosis, we previously examined the effects of aging on mucosal apoptosis in the gastric and colonic mucosa of Fischer 344 rats. We reported that the number of mucosal cells in the stomach and colon undergoing apoptosis, as determined by TUNEL assay, decreases with advancing age (22,35). In the colonic mucosa, this was further supported by the observation that with aging, there was a reduction in proapoptotic Bak and stimulation of antiapoptotic Bcl-xL as well as activation of caspase-3, -8, and -9 (35).…”

Section: Discussionmentioning

confidence: 63%

“…In recent years, studies from this and other laboratories have demonstrated that in Fischer 344 rats, aging is associated with increased mucosal proliferative activity in much of the gastrointestinal tract, including the colon (1, 9, 10 -12, 20, 21, 35). In contrast, the numbers of cells undergoing apoptosis, as determined by TdT-mediated dUTP nick end-labeling (TUNEL) assay, were found to decrease in the gastric and colonic mucosa during aging in Fischer 344 rats (22,35). Further support for the age-related decline in apoptosis in the colonic mucosa was provided by the observation that aging also resulted in decreased levels of the proapoptotic protein Bak, diminished activity of caspases, and increased levels of antiapoptotic Bcl-xL protein (35).…”

mentioning

confidence: 99%

“…In contrast, the numbers of cells undergoing apoptosis, as determined by TdT-mediated dUTP nick end-labeling (TUNEL) assay, were found to decrease in the gastric and colonic mucosa during aging in Fischer 344 rats (22,35). Further support for the age-related decline in apoptosis in the colonic mucosa was provided by the observation that aging also resulted in decreased levels of the proapoptotic protein Bak, diminished activity of caspases, and increased levels of antiapoptotic Bcl-xL protein (35). Because induction of proliferation and inhibition of apoptosis are associated with the development and progression of carcinogenesis, it has been suggested that aging may predispose the gastrointestinal tract to neoplasia (1,12,21,22).…”

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confidence: 99%

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Phosphatidylinositol 3-kinase/Akt signaling stimulates colonic mucosal cell survival during aging

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Although aging is shown to be associated with decreased apoptosis and increased survival of cells in the colonic mucosa of Fischer 344 rats, the regulatory mechanisms are poorly understood. The current investigation examines the involvement of phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway in mediating the events of colonic mucosal cell survival during aging. We have observed that aging is associated with activation of PI3K/Akt signaling, as evidenced by the higher levels of phosphorylated forms of p85, the regulatory subunit of PI3K and of Akt in the proximal and distal colonic mucosa, of aged (21–23 mo) than in young (4–7 mo) rats. These increases are accompanied by a concomitant rise in phosphorylation of proapoptotic protein Bad, which is sequestered by the 14-3-3 family of proteins following phosphorylation by Akt, resulting in a reduction in nonphosphorylated Bad. The amount of antiapoptotic Bcl-xL bound to nonphosporylated Bad in the colonic mucosa is found to be substantially lower in aged than in young rats, resulting in a marked rise in the unbound/free form of Bcl-xL in the aging colon. The age-related activation of PI3K and the reduction in caspase-3 activity could be reversed by wortmannin, a specific inhibitor of PI3K. Increased levels of Bcl-xL and phosphorylated forms of Akt and Bad and reduction in caspase-3 activity were observed throughout the entire length of the colonic crypt of aged rats. We conclude that the constitutive activation of the PI3K/Akt-signaling pathway is partly responsible for the age-related increase in colonic mucosal cell survival. This is evident throughout the entire length of the colonic crypt.

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Section: Discussionmentioning

confidence: 63%

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confidence: 99%

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confidence: 99%

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Phosphatidylinositol 3-kinase/Akt signaling stimulates colonic mucosal cell survival during aging

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Determination of proliferating cell nuclear antigen (PCNA) immunoreactivity, as a measure of proliferative activity, was done as described previously (37). Briefly, sections were deparaffinized and microwaved in citrate buffer for antigen retrieval.…”

Section: Methodsmentioning

confidence: 99%

Regression of Early and Intermediate Stages of Colon Cancer by Targeting Multiple Members of the EGFR Family with EGFR-Related Protein

Schmelz

Sengupta

et al. 2007

Cancer Research

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A role of the epidermal growth factor receptor (EGFR) family has been suggested in colon cancer etiology, progression, and/ or severity. Our recently identified pan-erbB inhibitor EGFRrelated protein (ERRP) targets EGFRs by attenuating their activation and subsequent signaling leading to cellular growth inhibition. In the present study, we evaluated the therapeutic effectiveness of ERRP on early and intermediate stages of colon cancer by examining regression of chemically induced aberrant crypt foci (ACF) in the colon of CF1 mice and intestinal adenomas in APC Min+/À (Min) mice. After formation of ACF or adenomas, the mice were injected (i.p.) with ERRP (50 Mg/mouse) for 10 consecutive days. This treatment significantly reduced the number of ACF from 25.0 F 3.0 (controls) to 14.9 F 1.6 (ERRP-treated; P = 0.011) and also reduced their size (P < 0.01). In Min mice, ERRP caused the regression of adenomas throughout the small intestine (P < 0.05) and reduced their size (P < 0.001). This could partly be attributed to inhibition of proliferation and stimulation of apoptosis in the intestinal mucosa and was associated with decreased activation of several EGFR family members, suppression of downstream effector nuclear factor KB and down-regulation of cyclooxygenase-2. ERRP-induced attenuation of EGFR activation could be due to increased sequestration of the ligand(s) by ERRP, rendering them unavailable for binding to and activation of the receptor. In conclusion, our data show that ERRP is effective in regressing both early and intermediate intestinal lesions and could be an effective therapeutic agent for colon cancer. [Cancer Res 2007;67(11):5389-96]

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“…The interpretation of the correlation between apoptosis and aging remains controversial. While several studies are consistent with apoptosis being upregulated during senescence in diverse cells, including cardiomyocytes (31), hepatocytes (32) and fibroblasts (33), other studies indicate that oxidative stress does not induce apoptosis in senescent cells (34) and that senescence may attenuate apoptosis (35). The different interpretations may have resulted from the variations in species, strains or cell types used in the respective studies.…”

Section: Discussionmentioning

confidence: 94%

Comparative analysis of various donor cell types for somatic cell nuclear transfer and its association with apoptosis and senescence

Kim

Hyun

2013

Molecular Medicine Reports

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Abstract. The aim of the present study was to characterize potential somatic cell nuclear transfer (SCNT) donor cells by comparing two lines of transfected cells with their non-modified parental controls in culture. Fetal fibroblasts used in the study originated from crossbred Landrace x Yorkshire x Duroc (LYD) or Yucatan mini-pigs. The LYD fibroblasts were modified by the transfection of a tetracycline on/off gene, whereas Yucatan fibroblasts were triple transfected with the complement regulatory factors, human decay-accelerating factor and human CD59, as well as H-transferase. At the 9th doubling passage, parameters associated with senescence and apoptosis, including morphology, mRNA expression (TP53, Bcl-2, Bax) and reactive oxygen species (ROS) levels, were evaluated. Population doubling (PD) time was calculated by assessing the time required for cell numbers to double by averaging the three cell passages. Quantitative polymerase chain reaction revealed that when comparing LYD with Yucatan fibroblasts, the latter exhibited a lower relative expression of TP53 and a higher relative expression of antiproliferative Bcl-2, which correlated with the PD time results (26 and 40 h, respectively). Tetracycline on/off transfected cell lines exhibited a lower relative expression of antiapoptotic Bcl-2 compared with their originating LYD cells. Similarly, triple transgenic cells exhibited higher TP53 and Bax mRNA expression levels than their non-transgenic counterparts. For ROS measurement, cells were incubated with 2',7'-dichlorofluorescin diacetate under the same conditions and were analyzed by flow cytometry. Yucatan fibroblasts exhibited higher ROS content than LYD cells. In addition, the two transgenic cell lines produced higher ROS levels than their corresponding non-transfected cell lines. In conclusion, these results indicate that characteristics associated with senescence and apoptosis in transfected cells during culture may affect the efficiency of SCNT when used as donor cells for the production of transgenic swine.

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Aging is associated with increased proliferation and decreased apoptosis in the colonic mucosa

Cited by 71 publications

References 29 publications

Phosphatidylinositol 3-kinase/Akt signaling stimulates colonic mucosal cell survival during aging

Phosphatidylinositol 3-kinase/Akt signaling stimulates colonic mucosal cell survival during aging

Regression of Early and Intermediate Stages of Colon Cancer by Targeting Multiple Members of the EGFR Family with EGFR-Related Protein

Comparative analysis of various donor cell types for somatic cell nuclear transfer and its association with apoptosis and senescence

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