TGF-β expression in the human colon: differential immunostaining along crypt epithelium

Avery, A. J.; Paraskeva, C; Hall, P. A.; Flanders, K. C.; Mb, Sporn; Moorghen, M

doi:10.1038/bjc.1993.301

Cited by 107 publications

(60 citation statements)

References 6 publications

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“…As these processes are critical in the maintenance of tissue homeostasis in the colonic crypt, it is somewhat surprising that relatively little is known about the specific role of the Rb protein in the colon. The differential expression of other proteins within the colonic crypt, for example Bcl-2 Bax, (Krajewski et al, 1994), TGFβ, (Avery et al, 1993), and IGFBP-3 (Williams et al, 2000), have given important clues as to their function in the regulation of crypt architecture. Therefore we investigated the expression of pRb in the normal colonic crypt in vivo, and the mechanism of regulation of pRb expression with differentiation and apoptosis in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…As differential expression of proteins along the axis of the normal colonic crypt has previously given important clues as to their function in the colonic crypt (for example Avery et al, 1993;Williams et al, 2000), the expression of pRb and related pocket proteins (p107 and p130) was investigated for at least 10 sections from different patients of normal colonic mucosa and tissue adjacent to colon tumours where appropriate. Blocking peptides for each antibody were used as a control to ensure that antibody staining was specific (refer to materials and methods, data not shown).…”

Section: Rb Protein and Related Proteins P107 And P130 Are Differentimentioning

confidence: 99%

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Transcriptional down-regulation of the retinoblastoma protein is associated with differentiation and apoptosis in human colorectal epithelial cells

et al. 2001

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SummaryThe aim of this study was to investigate the regulation of Rb protein expression in relation to increased differentiation and induction of apoptosis in colonic epithelial cells. In vivo, Rb protein expression was found to be down-regulated towards the top of the normal colonic crypt, coincident with the region of differentiation and apoptosis, but highly expressed in colonic carcinoma tissue. Using in vitro models to study the regulation of Rb expression in pre-malignant colonic epithelial cells, we have been able to show for the first time that Rb protein expression is transcriptionally down-regulated in differentiated pre-malignant cells (in post-confluent cultures) but not in malignant colorectal epithelial cells. Furthermore, suppression of rb protein function by the HPV-E7 viral oncoprotein increased both spontaneous and DNA damage-induced apoptosis. These results suggest that Rb is able to act as a survival factor in colonic epithelial cells by suppressing apoptosis, and that over-expression of pRb in colorectal tumour cells can cause a loss of sensitivity to apoptotic signalling, resulting in aberrant cell survival and resistance to therapy. targeted inactivation of the RB-1 gene in mouse embryonic fibroblasts induces apoptosis. Therefore, pRb appears to suppress apoptosis in some cell systems, perhaps through the sequestration of the E2F-1 protein, which can induce apoptosis if over-expressed (Qin et al, 1994;Field et al, 1996). In this case, pRb needs to be removed or inactivated before apoptosis can occur. To support this, a 30 kD protein has been detected in apoptotic cells harvested from colon tumour cell lines, CMSV40 fibroblasts and BJA-B lymphocyte cells, suggesting that the Rb protein is cleaved during the apoptotic process (Browne et al, 1994;An and Dou, 1996). Furthermore, cleavage at the C-terminus of pRb results in a p100 and ~5 kDa polypeptide (Chen et al, 1997). The p100 Rb protein can still bind to E2F-1 and inhibit E2F-mediated transcriptional activity, but its anti-apoptotic function is reduced, perhaps through its inability to bind to the oncogene MDM2. Thus the growthsuppressive and anti-apoptotic functions of pRb appear to be distinct from one another. The notion that pRb functions can be separated from one another has been explored previously, and experimental evidence indicates that the multiple functions of pRb can be genetically uncoupled, providing distinct functions in cellcycle control or in tissue-specific gene expression during differentiation (reviewed in Yee et al, 1998). Mice with mutations of the N-terminal region of Rb protein exhibit defects in muscle differentiation, whilst retaining the ability to bind to E2F (Riley et al, 1997). Conversely, cells with pRb mutations in the pocket domain are able to differentiate normally even when E2F binding is abrogated (Sellers et al, 1998).The functional loss of the Rb protein, by deletion or mutation, has been implicated not only in retinoblastoma, but in many types of tumour, including bladder, breast, lung and ovarian ca...

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Section: Discussionmentioning

confidence: 99%

Section: Rb Protein and Related Proteins P107 And P130 Are Differentimentioning

confidence: 99%

Transcriptional down-regulation of the retinoblastoma protein is associated with differentiation and apoptosis in human colorectal epithelial cells

et al. 2001

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“…sodum butyrate, to proceed through a differentiation programme. Indeed, the presence of TGFb 1 protein expression in the non-proliferating region of the human colonic cryptic (Avery et al, 1993), may suggest a role for the growth factor in mediating a stable growth arrest which is a prerequisite for differentiation. In addition, differentiating agents such as HMBA, retinoid acid and sodium butyrate can induce TGFb 1 expression (Glick et al, 1989;Schroy et al, 1990;Barnard and Warwick, 1993) suggesting some interaction between these factors in the maintenance of a differentiated phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…This autocrine growth inhibitor has been demonstrated to negatively regulate intestinal epithelial cell growth in vitro (Barnard et al, 1989;Hoosein et al, 1989;Manning et al, 1991;Geiser et al, 1992;Wu et al, 1992). In addition, immunostaining for TGFb 1 protein expression in the normal human colonic mucosa has shown it to be differentially expressed within epithelial cells of the crypt, with enhanced immunoreactivity in the non-proliferating more differentiated cells in the upper parts of the crypt and an absence of expression in the lower proliferating cell compartment (Avery et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Butyrate- but not TGFβ1-induced apoptosis of colorectal adenoma cells is associated with increased expression of the differentiation markers E-cadherin and alkaline phosphatase

1997

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Sodium butyrate and transforming growth factor b (TGFb 1 ) are growth inhibitory to colonic adenoma cell lines. Butyrate induces apoptosis, whereas in some adenoma cell lines, TGFb 1 can be growth inhibitory without apoptosis. In this report, we show that the adenoma cell line PC/BH/C1 undergoes apoptosis in response to TGFb 1 . Butyrate induced cell death is preceded by the induction of two markers of colonic differentiation ± alkaline phosphatase (ALP) activity and E-cadherin protein expression. However, TGFb 1 -induced apoptosis was not accompanied by induction of these differentiation markers. It is possible that the apoptosis induced by TGFb 1 in the adenoma cell line PC/BH/C1 is due to conflicting signals, as downregulation of c-myc protein in response to TGFb 1 occurs only slowly in this cell line. Development of resistance to TGFb 1 in colonic tumours may involve two separate stages ± resistance to growth inhibition and resistance to TGFb 1 -induced apoptosis. Our results indicate that sodium butyrate induces apoptosis via differentiation, but TGFb 1 induces apoptosis by a differentiationindependent mechanism. As for butyrate, the induction of Ecadherin expression is a potentially important chemopreventative action, since increased E-cadherin expression has been correlated with decreased metastatic potential. This is the first report of induction of E-cadherin by a naturally occurring factor in the diet. Butyrate may reduce tumour growth and invasion, not only as a result of the induction of apoptosis, but also through increased expression of E-cadherin.

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“…Evidence for such a molecule has been far from conclusive . Studies investigating extrinsic controls have included factors such as TGF␣ (Avery et al, 1993) and cell adhesion molecules (Beaulieu, 1992). Investigators have reported spatially regulated expression of such factors along the crypt-villus axis or along the crypt column.…”

Section: Discussionmentioning

confidence: 99%

Epithelial cell dynamics in rabbit cecum and proximal colon P1

Grant

Specian

2001

Anat. Rec.

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The large intestine of mammals has long been viewed as an osmoregulatory organ, and evidence suggests that fluid and solute transport mechanisms within the intestine are heterogenous, varying depending on the particular segment involved. Variations in function are often matched by morphological correlates, but despite the widespread use of rabbit large intestine as an experimental model, there is a lack of knowledge about the cellular makeup and dynamics in the colonic mucosal epithelium. The presence of mitotic figures and immunohistochemical localization of proliferating cell nuclear antigen (PCNA) were used to identify the proliferative zone(s). Cellular migration patterns were determined through the use of the thymidine analog 5-bromo-2-deoxyuridine (BrdU) over a 24-, 48-, and 72-hr period. Apoptotic nuclei were identified utilizing terminal deoxynucleotidyl transferase d-UTP nick-end labeling (TUNEL). Both cecum and the initial portion of the proximal colon (P1) exhibited a proliferative zone at or near the crypt base, and migration proceeded upwards toward the surface epithelium lining the intestinal lumen, where apoptosis occurred Turnover time of crypt columnar cells was determined to be about 3 days; that of mucous cells was estimated to be about 5 weeks. Rabbit cecum and proximal colon P1 are similar in their cellular morphology and epithelial cell kinetics. In both, the major proliferative zone is located at or near the crypt base, from which crypt columnar cells migrate toward the lumenal surface epithelium over a period of 3 days. Goblet cell turnover rate is much slower than that of columnar cells.

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TGF-β expression in the human colon: differential immunostaining along crypt epithelium

Cited by 107 publications

References 6 publications

Transcriptional down-regulation of the retinoblastoma protein is associated with differentiation and apoptosis in human colorectal epithelial cells

Transcriptional down-regulation of the retinoblastoma protein is associated with differentiation and apoptosis in human colorectal epithelial cells

Butyrate- but not TGFβ1-induced apoptosis of colorectal adenoma cells is associated with increased expression of the differentiation markers E-cadherin and alkaline phosphatase

Epithelial cell dynamics in rabbit cecum and proximal colon P1

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