The adenomatous polyposis coli (APC) tumour suppressor – genetics, function and disease

Sieber, Oliver M.; Tomlinson, Ian; Lamlum, Hanan

doi:10.1016/s1357-4310(00)01828-1

Cited by 110 publications

(80 citation statements)

References 64 publications

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“…This property of APC resides in the N-terminal portion of the protein, thereby also encompassing mutant forms lacking NLS1 APC and NLS2 APC . Since biallelic loss of APC is a rare event in tumor development (Rowan et al, 2000), a selective pressure for the retention of some N-terminal functions of APC in tumor cells has been proposed (Rowan et al, 2000;Sieber et al, 2000;Fodde et al, 2001b). In view of the present findings that both wild-type and truncated APC accumulate only in the nucleus of proliferating cells throughout the cell cycle, we suggest that an involvement of APC in nuclear growth control mechanism(s) might be one such function.…”

Section: Discussionmentioning

confidence: 55%

Nuclear accumulation of full-length and truncated adenomatous polyposis coli protein in tumor cells depends on proliferation

et al. 2003

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The adenomatous polyposis coli (APC) tumor suppressor is a nucleocytoplasmic protein. The nuclear accumulation of APC was recently found to vary depending on cell density, suggesting that putative APC function(s) in the nucleus is controlled by the establishment of cell contacts. We report here that the density-dependent redistribution of APC between nucleus and cytoplasm prevails in 6/6 thyroid and colorectal carcinoma cell lines. Moreover, mutated APC lacking known nuclear localization sequences had the similar distribution pattern as the fulllength protein. APC invariably accumulated in the nuclei of Ki-67 expressing cells, but was largely cytoplasmic when cell cycle exit was induced by serum starvation or at high cell density. APC colocalized with b-catenin in the nucleus only in one cell line (SW480). Also, APC maintained a predominantly nuclear position in early confluent states when cytoplasmic b-catenin was recruited to newly formed adherens-like junctions. The results indicate that nuclear targeting of APC is driven by cell cycle entry rather than altered cell-cell contact. The ability of C-terminally truncated APC to accumulate in the nucleus suggests that nuclear import signals other than NLS1 APC and NLS2 APC are functionally important. Residual function(s) of N-terminal APC fragments in tumor cells carrying APC mutations might be beneficial to tumor growth and survival.

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Section: Discussionmentioning

confidence: 55%

Nuclear accumulation of full-length and truncated adenomatous polyposis coli protein in tumor cells depends on proliferation

et al. 2003

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“…The upregulation of expression at such an early stage in neoplasia might imply an important role for PKR in colonic epithelial transformation, again, either as a pro-neoplastic agent or as a response to the earliest changes of cancer formation. One of the first genetic alterations in the colonic adenoma-carcinoma sequence is mutation of the APC gene (Adenomatous Polyposis Coli) that is thought to activate a number of oncogenic proteins, such as c-myc (Sieber et al, 2000). Since PKR has been shown to play a tumor suppressive role in response to activation of this oncogene (Raveh et al, 1996;Shang et al, 1998), one could hypothesize its upregulation on this basis.…”

Section: Discussionmentioning

confidence: 99%

Neoplastic progression in melanoma and colon cancer is associated with increased expression and activity of the interferon-inducible protein kinase, PKR

et al. 2002

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The interferon-inducible, double-stranded RNA (dsRNA)-activated protein kinase, PKR, plays key roles in regulation of cell growth and differentiation, and has been postulated as a tumor suppressor. Downstream effectors of PKR include the translation initiation factor, eIF2a, and the transcription factor, NF-kB. We found elevated levels of PKR protein, dsRNA-dependent PKR autophosphorylation activity, and phosphorylated eIF2a in melanoma cells compared to nontransformed melanocytes in culture. Treatment with interferon-a2b further induced PKR expression and activity. Immunohistochemical analysis of primary melanomas demonstrated minimal PKR immunoreactivity, but melanoma lymph node metastases expressed a high level of PKR protein. Furthermore, analysis of colon cancer specimens revealed that transformation from normal mucosa to adenomas and carcinomas was coincident with an increase in PKR expression. These data do not support the concept of PKR as a classic tumor suppressor but instead suggest that PKR upregulation occurs at defined steps in cancer progression, probably as a cellular response to neoplasia.

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“…This loss of expression observed in human primary tumors, as well as in cell lines, is essentially due to promoter methylation (Bernet et al, 2007;Shin et al, 2007). Furthermore, Bernet and colleagues took advantage of a natural UNC5H3 loss-of-function occurring in mice (rcm, rostral cerebellar malformation) to demonstrate that UNC5H3 loss of function is associated with tumor progression: mice that carry the APC 1638N germline mutation, known to predispose mice to the development of low-grade adenoma (Sieber et al, 2000), and are heterozygous or homozygous for mutant UNC5H3, develop adenomas that progress to adenocarcinoma at a higher frequency than what is seen in APC 1638N mice. Interestingly, loss of UNC5H3 function in mice also correlates with apoptosis reduction in mice tumors.…”

Section: Drs Are Altered During Tumor Progressionmentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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Dependence receptors (DRs) now form a family of more than a dozen membrane receptors that are not linked by their structure, but by common functional traits. The most notable is their ability to trigger two opposite signaling pathways: in the presence of ligand, these receptors activate classic signaling pathways implicated in cell survival, migration and differentiation. In the absence of ligand, they do not stay inactive, rather they elicit an apoptotic signal. Thus, cells expressing this kind of receptor are dependent on the presence of ligand in the extracellular environment to survive. This review will recapitulate the increasing data regarding the molecular mechanisms associated with DRs, their potential implication during development, as well as their deregulation during tumorigenesis and, finally, their emergence as new possible therapeutic targets for cancer treatment.

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The adenomatous polyposis coli (APC) tumour suppressor – genetics, function and disease

Cited by 110 publications

References 64 publications

Nuclear accumulation of full-length and truncated adenomatous polyposis coli protein in tumor cells depends on proliferation

Nuclear accumulation of full-length and truncated adenomatous polyposis coli protein in tumor cells depends on proliferation

Neoplastic progression in melanoma and colon cancer is associated with increased expression and activity of the interferon-inducible protein kinase, PKR

Dependence receptors: a new paradigm in cell signaling and cancer therapy

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