From differentiation to proliferation: The secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells

Pietrzik, Claus U.; Hoffmann, Jens; Stober, K; Chen, Chunyan; Bauer, Christoph; Otero, Deborah A. C.; Roch, Jean‐Marc; Herzog, Volker

doi:10.1073/pnas.95.4.1770

Cited by 87 publications

(88 citation statements)

References 34 publications

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“…Gain-of-function studies showed that APP overexpression leads to increased cellular proliferation (12,17,42). Lossof-function studies either by APP knockdown (14,16,17) or blockage of sAPP function by antibody application (15) demonstrated regression of carcinoma growth in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…These results clearly indicate that the secreted N-terminal domain of APP plays an essential regulatory role in promoting cellular growth. Several lines of evidence showed that sAPP␣ fulfills criteria of a trophic growth factor (42,45,(57)(58)(59) and that the growth regulating activity of APP is specified to the N-terminal domain of sAPP containing the 5-amino acid sequence RERMS (APP-(328 -332)). Peptides containing this pentapeptide sequence could increase cellular proliferation in fibroblasts and induce FIGURE 6.…”

Section: ␤-Amyloid Precursor Protein Is a Tumor Growth Factormentioning

confidence: 99%

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Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

111

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The ␤-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APP␣. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP downregulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy. ␤-Amyloid precursor protein (APP)2 is a highly conserved single transmembrane protein (type I) with a receptor-like structure and consists of a heterogeneous group of proteins migrating between 110 and 135 kDa (1, 2). The heterogeneity is due to alternative splicing, leading to eight distinct isoforms (namely APP677, APP695, APP696, APP714, APP733, APP751, APP752, and APP770), as well as by a variety of post-translational modifications, including O-and N-glycosylation, sulfation, and phosphorylation. APP isoforms exist as immature (N-glycosylated) and mature (N-and O-glycosylated, tyrosylsulfated) species. Immature APP localizes in the endoplasmic reticulum and cis-Golgi, and the mature APP form preferentially localizes in the trans-Golgi network, secretory and endocytic vesicles, and at the plasma membrane (3, 4).APP695 is the most common isoform in the central nervous system, whereas APP751 and APP770 are predominantly expressed in non-neuronal cells (5). The key event in the pathogenic cascade in Alzheimer disease is the amyloidogenic pathway characterized by subsequent cleavage of APP by the enzyme ␤-secretase and further processing by ␥-secretase, which finally leads to the generation of A␤ peptides. However, the predominant route of APP processing consists of successive cleavages by ␣-and ␥-secretases in non-neuronal cells (6, 7). The cleavage of APP at Lys 16 -Leu 17 bond by ␣-secretase within the A␤ sequence ...

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Section: Discussionmentioning

confidence: 99%

Section: ␤-Amyloid Precursor Protein Is a Tumor Growth Factormentioning

confidence: 99%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

111

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“…Therefore, APP can influence the cellular growth not only via its trophic domain amino acids sequence but also via a mechanism that is still undefined at present. The sAPP has been reported to activate ERKs in a Rasdependent fashion, 7,10 and an amino-terminal region of sAPP, which is distinct from the trophic domain mentioned above, is responsible for this effect, though the precise underlying mechanisms for sAPP internalization and/or interaction of sAPP with ERKs signaling pathway are largely uncertain. 10,11 In accordance with these observations, overexpression of APP in neuroectodermal cells resulted in a steady-state hyperactivation of ERK2.…”

Section: Reduced Tumor Growth Of App Antisense Clones In Nude Micementioning

confidence: 99%

“…Given the previous observations that APP could have an important role in the growth of fibroblasts and certain epithelial cells, 6,7 it is reasonable to postulate that APP has a crucial role in the cellular growth and survival of not only neural cells 1 but also non-neural cells including carcinoma cells. Understanding the mechanism underlying the effect of APP on the growth of carcinoma cells would also shed light on the undetermined physiological function of this ubiquitous protein in nonneural cells.…”

Section: Reduced Tumor Growth Of App Antisense Clones In Nude Micementioning

confidence: 99%

“…1 Saitoh et al 6 showed that APP can be a potent growth factor for fibroblasts as well as for thyroid follicular epithelial cells. 7 Although the precise mechanism underlying the growth-promoting effect of APP on fibroblasts remains to be clarified, functional mapping of APP revealed that an internal peptide sequence of 5 amino acids, RERMS corresponding to APP328-332, represents the minimal active domain for this growth-promoting effect. 8,9 On the other hand, N-terminal region of sAPP has been shown to activate mitogen-activated protein kinase (MAPK), also known as extracellular signal-regulated kinase (ERK).…”

mentioning

confidence: 99%

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Amyloid β protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo

Jingyan¹,

Kataoka²,

Itoh³

et al. 2001

Int. J. Cancer

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Amyloid ␤ protein precursor (APP) is a membrane-bound protein ubiquitously expressed in a variety of types of cells. However, its biological functions remain largely uncertain, particularly in non-neural cells and tumors. Our previous studies revealed that a secreted form of APP having a Kunitztype inhibitor domain is a major serine proteinase inhibitor secreted by human colon carcinoma cells. In our study, we used an antisense RNA strategy to selectively inhibit the expression of APP in the human colon carcinoma cell line SW837. A vector capable of expressing an antisense mRNA complementary to 911 bases of the 5 end of APP mRNA was transfected into SW837 cells. After selection, 2 stably transfected antisense clones were obtained in which both the APP protein and mRNA were significantly suppressed. The proliferative potential and colony-forming efficiency of the antisense clones in vitro were markedly suppressed compared with the parent and mock-transfected clones. The addition of the conditioned medium of parent cells or purified secretory APP enabled these antisense effects to be overcome in vitro. The suppressed growth was also observed in vivo when the cells were injected subcutaneously into nude mice. Histologically, formation of tubular structures appeared to be suppressed in the antisense clones in vivo. These observations suggest potentially important roles of APP in cellular proliferation and differentiation of colon carcinoma cells. Key words: amyloid ␤ protein precursor; colon carcinoma cell; antisense; growthAmyloid ␤ protein precursor (APP) is a large precursor protein of ␤-amyloid found in neurite plaques of Alzheimer's disease, and it exists in multiple isoforms as a result of alternative splicing of the 19 exons encoded by the APP gene. 1 With regard to exons, exon 7 encodes for 57 amino acids with considerable homology to a Kunitz-type serine proteinase inhibitor, and the secreted protein containing the inhibitor domain is identical to proteinase nexin-II, which was initially isolated from human fibroblasts by its property of forming complexes with epidermal growth factor-binding protein. 2 APP is a ubiquitous protein and synthesized by most cells throughout the body. 1 However, its biological functions are largely unknown, particularly in non-neural tissues. Previously, we reported that human tumor cell lines consistently secreted highmolecular weight trypsin inhibitors, which were identical to the secreted form of APP (sAPP) with Kunitz domain. 3,4 Indeed, sAPP represented the major trypsin inhibitor produced by a panel of colon carcinoma cell lines. 5 This evidence suggests that APP and/or sAPP may have important, though undefined, biological functions in tumor cells, including colon carcinoma cells.To date, a limited amount of evidence is available for the possible role of APP in non-neural cells and essentially nothing is known about its function in tumors of systemic organs. 1 Saitoh et al. 6 showed that APP can be a potent growth factor for fibroblasts as well as for thyroid follicular e...

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Amyloid β protein precursor is involved in the growth of human colon carcinoma cellin vitro andin vivo

et al. 2001

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From differentiation to proliferation: The secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells

Cited by 87 publications

References 34 publications

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Amyloid β protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo

Amyloid β protein precursor is involved in the growth of human colon carcinoma cellin vitro andin vivo

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