Inactivating mutations of caspase-8 gene in colorectal carcinomas

Kim, Hong Sug; Lee, Jong Woo; Soung, Young Hwa; Park, Won Sang; Kim, Su Young; Park, Jik Young; Cho, Youg Gu; Kim, Chang Jae; Jeong, Seong Whan; Nam, Suk Woo; Kim, Sang Ho; Lee, Jung Young; Yoo, Nam Jin; Lee, Sug Hyung

doi:10.1016/s0016-5085(03)01059-x

Cited by 208 publications

(181 citation statements)

References 25 publications

Supporting

Mentioning

174

Contrasting

Order By: Relevance

“…On the contrary, CASP8 mutations have been detected in 5% of invasive colorectal carcinomas (but not adenomas), and are associated with dominant-negative caspase-8 function and decreased apoptosis. 164 Somatic mutation of CASP8 has also been detected in hepatocellular carcinomas (HCCs) 165 and advanced gastric cancers, 166 and are associated with decreased cell death. 165 Interestingly, a CASP8 polymorphism (D302H) is associated with significantly reduced overall risk breast cancer.…”

Section: Caspases In Tumorigenesismentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

View full text Add to dashboard Cite

Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

show abstract

Section: Caspases In Tumorigenesismentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

View full text Add to dashboard Cite

show abstract

“…35 CASP8 mutations have also been detected, albeit at relatively low frequency, in colorectal and gastric cancers. 36,37 An identical somatic frameshift mutation (1225-1226delTG) resulting in premature amino-acid synthesis termination in the p10 protease subunit was found in nine out of 69 patients suffering from hepatocellular carcinoma. 38 Moreover, even though DISCmediated apoptosis is considered to be an important regulator of the immune response by controlling the number of activated T-and B-cells, protection against this selection seems to ensure the maintenance of CD34 þ hematopoietic progenitors.…”

Section: Do Individual Caspases Have Tumor Suppressor Functions?mentioning

confidence: 99%

Caspases and cancer

2011

View full text Add to dashboard Cite

Evasion of apoptosis is considered to be one of the hallmarks of human cancers. This cell death modality is executed by caspases and several upstream regulatory factors, which direct their proteolytic activity, have been defined as either tumor suppressors or oncogenes. Often these regulatory factors, in addition to being potent apoptosis inducers, function in cell survival or repair signaling pathways in response to cellular stress. Thus, loss of function in a distinct regulatory mechanism does not necessarily mean that tumor formation is due to apoptosis malfunction resulting from insufficient caspase activation. Although each caspase has been assigned a distinct role in apoptosis, some redundancy with respect to their regulatory functions and substrate recognition is evident. Jointly, these proteases could be considered to possess solid tumor suppressor function, but what is the evidence that deregulation of specific caspases per se induces inappropriate cell survival, leading to enhanced tumorigenic potential? This question will be addressed in this review, which covers basic molecular mechanisms derived from in vitro analyses and emphasizes new insights that have emerged from in vivo and clinical studies. In organisms, excess cells during development, as well as potentially harmful cells resulting from pathophysiological conditions, are eliminated by various cell death modalities. Among them, apoptosis is the most investigated, and almost 40 years ago, it was described as a major defense strategy that prevents cells from acquiring tumorigenic potential. 1 This suicide mechanism is controlled by multiple and interrelated pathways ensuring that caspases, the proteolytic initiators and executioners of apoptosis, are triggered only in cells requiring termination. There is overwhelming experimental evidence supporting the idea that disturbances in the regulation of caspase activation are central for the avoidance of cancer cell death, both in vitro and in vivo. However, what evidences suggest that caspases per se act as tumor suppressors? It was reported that cells do not necessarily undergo caspaseindependent cell death in the absence of active caspases, but may instead survive insult and even promote clonogenic tumor growth. 2 Yet, it was unclear which individual caspases could fulfill this function. Recently, certain initiator caspases have been suggested as putative tumor suppressor genes. 3,4 This review is focusing on caspases and their role in tumor suppression, and emphasizing new evidences that have emerged from in vivo observations and clinical material, taking into consideration supporting in vitro data that has enlightened basic molecular mechanisms. CaspasesClassification of human caspases is based either on their function, the size of their pro-domain or cleavage specificity.Considering the first criteria, caspase-1, -4 and -5 belong to the group I (inflammatory) caspases that are involved in cytokine maturation. These proteases are primarily associated with the innate immunity against pathogens an...

show abstract

“…Current literature suggests that premalignant dysplasia is characterized by an increased percentage of proliferating cells (Johnston et al, 1989;Diebold et al, 1992). However, the role of apoptosis in colorectal cancer (CRC) carcinogenesis remains poorly understood (Kim et al, 2003). Advances in our understanding of these complementary processes are important to support the development of novel preventative and therapeutic strategies for CRC.…”

Section: Introductionmentioning

confidence: 99%

Modulation of CDK2-AP1 (p12DOC−1) expression in human colorectal cancer

et al. 2005

View full text Add to dashboard Cite

We have previously demonstrated an association between microsatellite instability and decreased CDK2-AP1 (p12 DOCÀ1 ) expression in human colorectal cancer (CRC) cell lines. In those same studies, induction of CDK2-AP1 expression promoted both cell cycle arrest and apoptosis. The goals of our present study were to better understand the mechanisms leading to reduced CDK2-AP1 expression in microsatellite unstable (MSI) CRC and to study further the effect of CDK2-AP1 modulation on cell proliferation and apoptosis utilizing RNA interference (RNAi) techniques. We used direct sequencing to screen for mutations of the poly (T)8 microsatellite-like region in the 3 0 end of the CDK2-AP1 gene in 24 CRC cell lines. We then utilized an in vitro human mismatch repair (MMR) recombinant system to assess for correction of the mutation and changes in CDK2-AP1 expression secondary to hMLH1 transfection. We also investigated the effect of CDK2-AP1 modulation in four settings: (1) native CDK2-AP1 absence, (2) endogenous CDK2-AP1 expression, (3) RNAi-induced CDK2-AP1 inhibition and (4) induced CDK2-AP1 over expression. The mutation -del T poly (T)8 -at the 3 0 end of the CDK2-AP1 gene was found in 3/12 (25%) of MSI CRC cell lines, but in none of the microsatellite stable samples (0/12). Interestingly, when wild-type MMR protein -MLH1 -was induced in an in vitro human recombinant system, the del T poly (T)8 mutation was reversed and CDK2-AP1 expression increased. RNAi-mediated CDK2-AP1 inhibition was associated with decreased apoptosis and increased cell proliferation in CDK2-AP1-non deficient CRC cell lines. We conclude that mutations in the microsatellite-like sequence of the CDK2-AP1 gene in MSI CRC are associated with decreased CDK2-AP1 expression. In addition, modulation of CDK2-AP1 expression in human CRC alters cell proliferation and apoptosis.

show abstract

Inactivating mutations of caspase-8 gene in colorectal carcinomas

Cited by 208 publications

References 25 publications

Old, new and emerging functions of caspases

Old, new and emerging functions of caspases

Caspases and cancer

Modulation of CDK2-AP1 (p12DOC−1) expression in human colorectal cancer

Contact Info

Product

Resources

About