The Ubiquitin-Proteasome Pathway an Emerging Anticancer Strategy for Therapeutics: A Patent Analysis

Jain, Chakresh Kumar; Arora, Shivam; Khanna, Aparna; Gupta, Money; Wadhwa, Gulshan; Sharma, Sanjeev Kumar

doi:10.2174/1574892810666150416111213

Cited by 9 publications

(7 citation statements)

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“…Ubiquitin, a polypeptide containing 76 amino acid residues, is a key regulatory factor in the cell cycle and is widely expressed in eukaryotes[10-13]. In recent years, a growing number of ubiquitin-related low-molecular-weight proteins, known as ubiquitin-like proteins, have been identified and are associated with a variety of cell processes[14-16]. So far, two ubiquitin-like protein families, ubiquitin-like modifiers (UBLs) and ubiquitin-domain proteins, have been identified[17-19].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological significance of human leukocyte antigen F-associated transcript 10 expression in colorectal cancer

Zhang¹,

Sun²,

Wang³

et al. 2019

WJGO

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BACKGROUND Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract. The worldwide mortality rate of CRC is about one half of its morbidity. Ubiquitin is a key regulatory factor in the cell cycle and widely exists in eukaryotes. Human leukocyte antigen F-associated transcript 10 (FAT10), known as diubiquitin, is an 18 kDa protein with 29% and 36% homology with the N and C termini of ubiquitin. The function of FAT10 has not been fully elucidated, and some studies have shown that it plays an important role in various cell processes. AIM To examine FAT10 expression and to analyze the relationship between FAT10 expression and the clinicopathological parameters of CRC. METHODS FAT10 expression in 61 cases of CRC and para-cancer colorectal tissues was measured by immunohistochemistry and Western blotting. The relationship between FAT10 expression and clinicopathological parameters of CRC was statistically analyzed. RESULTS Immunohistochemical analysis showed that the positive rate of FAT10 expression in CRC (63.93%) was significantly higher than that in tumor-adjacent tissues (9.84%, P < 0.05) and normal colorectal mucosal tissue (1.64%, P < 0.05). Western blotting also indicated that FAT10 expression was significantly higher in CRC than in tumor-adjacent tissue ( P < 0.05). FAT10 expression was closely associated with clinical stage and lymphatic spread of CRC. FAT10 expression also positively correlated with p53 expression. CONCLUSION FAT10 expression is highly upregulated in CRC. FAT10 expression is closely associated with clinical stage and lymphatic spread of CRC.

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Section: Introductionmentioning

confidence: 99%

Clinicopathological significance of human leukocyte antigen F-associated transcript 10 expression in colorectal cancer

Zhang¹,

Sun²,

Wang³

et al. 2019

WJGO

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“…Proteins are first ubiquitylated through 3 main steps: activation, conjugation and ligation, performed by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s), respectively; ubiquitylated proteins are then degraded by proteasomes. E3 ubiquitin ligases catalyze the final, but key step of the ubiquitination cascade through the specific recognition of the substrate target protein and E2 (1,2). It has been found that the RING-finger family is a major member of the E3 family.…”

Section: Introductionmentioning

confidence: 99%

Cullinï¿½7 is a predictor of poor prognosis in breast cancer patients and is involved in the proliferation and invasion of breast cancer cells by regulating the cell cycle and microtubule stability

Qiu

Zhang

et al. 2017

Oncol Rep

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Cullin 7 is the 'scaffold' of the cullin-RING-based E3 ligases which catalyze the final step of the ubiquitination cascade in eukaryotic organisms. Although one study has reported the involvement of cullin 7 in the invasion and migration of breast cancer cells without further exploration of its mechanisms, the expression of cullin 7 in breast cancer tissues and its clinical significance have not been reported. The present study evaluated cullin 7 protein expression in malignant and benign breast tissues using immunochemistry, and further analyzed the association of positive cullin 7 expression in breast cancer tissues with clinicopathological characteristics of breast cancer patients. Cullin 7 expression was further silenced in breast cancer cells by siRNA and its functions and mechanisms in cell proliferation and invasion were investigated. The results showed that high cullin 7 expression was significantly correlated with pathological stage (P=0.013) and lymph node metastasis (P=0.022) of breast cancer. Patients with high cullin 7 expression had a shorter overall survival rate than those with low cullin 7 expression (P=0.037). Silencing of cullin 7 expression significantly inhibited the proliferation (P<0.05) and invasion (P<0.05), increased S1 phase (P<0.05), but decreased G2 phase (P<0.05) in MDA-MB-231 and BT549 cells. In addition, silencing of cullin 7 expression decreased cyclin A, but increased p21 protein expression. Moreover, silencing of cullin 7 expression altered the cell shape, caused disorder in microtubules, and increased the microtubule regeneration in MDA-MB-231 and BT549 cells. In conclusion, cullin 7 is overexpressed in breast cancer tissues which is associated with the development and prognosis of breast cancer. Cullin 7 is involved in the proliferation and invasion of breast cancer cells by regulating the cell cycle and microtubule stability.

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“…The proteasomal degradation of some proteins can be promoted by phosphorylation [43]. To investigate the role of PIKKs in this phenomenon, HEK293 cells were pre-treated with wortmannin or LY294002 for 30 min and then treated with MMC for 6 h. Wortmannin is a broad inhibitor of PIKKs that irreversibly inhibits DNA-PK and ATM, whereas LY294002 is a potent inhibitor of class I phosphoinositide 3-kinases but does not efficiently inhibit PIKKs even at high concentrations [42, 44].…”

Section: Resultsmentioning

confidence: 99%

PICT-1 is a key nucleolar sensor in DNA damage response signaling that regulates apoptosis through the RPL11-MDM2-p53 pathway

et al. 2016

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PICT-1 is an essential ribosome biogenesis factor whose loss induces p53 accumulation and apoptosis. Here, we show that DNA damage changes PICT-1 localization and decreases PICT-1 protein levels via the proteasome pathway. Two important phosphatidylinositol 3-kinase-like kinases (PIKKs), ataxia-telangiectasia mutated (ATM) and the Ku70 subunit of DNA-dependent protein kinase (DNA-PK), co-localize and interact with PICT-1 in the nucleolus. Computational prediction of phosphorylation sites and detection using an anti-phospho-substrate antibody suggest that PICT-1 might be a substrate of PIKKs. PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1. PICT-1(S233A, T289A) demonstrated marked resistance to DNA damage-induced agglomeration and loss of PICT-1. Phosphomimetic PICT-1 (S233D, T289D) showed a different nuclear distribution and was more rapidly degraded after DNA damage than wild-type PICT-1. Furthermore, both phosphorylation and degradation of PICT-1 released RPL11 from the nucleolus to the nucleoplasm, increased binding of RPL11 to MDM2, and promoted p53 accumulation and apoptosis in an ATM-dependent manner after DNA damage. These data indicate that PICT-1 is a major nucleolar sensor of the DNA damage repair response and an important upstream regulator of p53 via the RPL11-MDM2-p53 pathway.

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The Ubiquitin-Proteasome Pathway an Emerging Anticancer Strategy for Therapeutics: A Patent Analysis

Cited by 9 publications

References 0 publications

Clinicopathological significance of human leukocyte antigen F-associated transcript 10 expression in colorectal cancer

Clinicopathological significance of human leukocyte antigen F-associated transcript 10 expression in colorectal cancer

Cullinï¿½7 is a predictor of poor prognosis in breast cancer patients and is involved in the proliferation and invasion of breast cancer cells by regulating the cell cycle and microtubule stability

PICT-1 is a key nucleolar sensor in DNA damage response signaling that regulates apoptosis through the RPL11-MDM2-p53 pathway

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