• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
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  • 2020-04
  • 2020-05
  • br Endothelial mechanotransduction br Apoptosis br Death ass


    Endothelial mechanotransduction
    Death associated protein kinase
    Conclusion DAPK is localized to the grazoprevir kinase network, and promotes actomyosin contractility. DAPK stabilizes stress fibers by phosphorylation of MLC (Bialik et al., 2004, Kuo et al., 2003). In endothelial cells DAPK phosphorylates TM-1 at Ser283 in response to ERK activation under oxidative stress (Houle et al., 2007). TM-1 is important in maintaining cardiovascular homeostasis, and its expression is lost in tumor cells (Bharadwaj et al., 2005). Furthermore, DAPK-regulated apoptosis pathway is suppressed during the angiogenic process. Netrin-1 is recently discovered to promote endothelial cell survival and angiogenesis by inhibiting its pro-apoptotic receptor UNC5B and its downstream regulator DAPK (Castets et al., 2009). Complete functions of DAPK are still being elucidated, which would further emphasize the importance of DAPK. The question remains, does fluid shear stress inhibits endothelial apoptosis by regulating DAPK expression? We begin to take a comprehensive look at DAPK as novel mechano-sensitive effectors of cellular responses through both functional and mechanistic analyses, by investigating the effects of shear stress on DAPK and TNFα induced apoptosis in endothelial cells (Rennier and Ji, 2012). We found a time-dependent effect of mechanical (shear stress) or biochemical (TNFα) induction on DAPK and apoptosis. DAPK could have other non-apoptotic functions in endothelial cells. The role of DAPK in apoptosis and its association with the actin cytoskeleton suggest it as a regulator of endothelial responses in mechanotransduction. DAPK can be potentially utilized by endothelial cells in affecting morphological changes in response to shear stress. The cytoskeleton effect of DAPK occurs before onset of apoptosis, and is independent of DAPK death domain. One potential model for this dual role of DAPK is that shear stresses regulate apoptotic function of DAPK in a time-dependent manner: the onset of shear stress will sequester DAPK to its cytoskeleton activities, and attenuate its ability to interact with subsequent stress-activated apoptotic binding partners. For example, shear stress increases binding of DAPK with cytoskeleton components TM-1 and MLC, while apoptotic cytokine will increase binding of DAPK with cytoplasmic partners to induce apoptosis.
    Conflict of interest statement
    Introduction Colorectal cancer is the most serious long-term complication in patients with chronic inflammatory bowel disease. Patients with long-standing ulcerative colitis (UC) are at increased risk of developing colorectal carcinoma (CRC) compared to the general population [13], [16], [31], with a prevalence of CRC of 5.4% for patients with pancolitis [13] and a cumulative incidence of CRC of 2.5% after 20 years, and of 7.6% after 30 years of duration of disease [40]. grazoprevir kinase The major risk factors independently associated with the development of dysplasia and CRC in UC are early onset, prolonged duration, and extensive colonic involvement of disease, as well as a high degree of mucosal inflammatory activity of UC [2], [3], [13], [16], [39], [40], [51]. As in sporadic colorectal carcinoma (SCC), neoplastic transformation in IBD follows an adenoma–carcinoma-sequence [55]. The molecular alterations that contribute to the development of SCC, i.e., chromosomal/microsatellite instability and hypermethylation, also play a role in UC-associated carcinogenesis [37]. However, there are distinct characteristics of UC-associated carcinoma (UCC) in the time of appearance and the frequency of key molecular alterations. Mutations in the APC and K-ras genes are less common and occur late in UCC [4], [5], [32], [48]. By contrast, p53 mutations and microsatellite instability are a frequent event and appear as early as in chronic inflamed mucosa of UC [5], [7], [20], [32], [44], [48], [57], [58]. Furthermore, it is well known that a group of SCC is characterized by a clustering occurrence of multiple hypermethylated genes, and is therefore known to exhibit a “CpG island methylator phenotype” (CIMP) [50]. This concordant methylation profile includes a series of cancer-related genes and is negatively associated with genetic aberrations of these tumors, suggesting that methylation can provide an alternative route for carcinogenesis [50], [53]. Also, for UC, hypermethylation of CpG island has been reported for some genes, such as p16, p14, E-cadherin, MGMT, HHP1, and the estrogene receptor gene [18], [19], [22], [33], [34], [41], [42], [54]. In UC, promoter methylation seems to precede dysplasia and occurs throughout the mucosa of colitis [18], [19], [22], [41], [42], [52]. However, data on the methylation status of UC-associated premalignant and neoplastic lesions are limited.