Role of Src-specific phosphorylation site on focal adhesion kinase for senescence-associated apoptosis resistance

Ryu, Sangwon; Cho, K. A.; Oh, Yoon Sin; Park, Seung Cheol

doi:10.1007/s10495-006-3978-9

Cited by 35 publications

(37 citation statements)

References 38 publications

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“…This is in agreement with other studies that have reported a decrease in induced apoptosis in old cells in response to different stimuli, including oxidative stress (Higami and Shimokawa 2000;Lee and Wei 2007) and γ-rays (Polyak et al 1997). Likewise, previous studies have shown that senescent fibroblasts are resistant to apoptosis induced by UV light (Ryu et al 2006) oxygen radicals (Gansauge et al 1997), serum withdrawal, H 2 O 2 , staurosporine, and thapsigargin (Wang 1995;Ryu et al 2006Ryu et al , 2007. On the other hand, other studies have shown that aging enhances apoptosis triggered by various challenges (Higami and Shimokawa 2000;Lee and Wei 2007).…”

Section: Discussionsupporting

confidence: 93%

Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress

Al‐Khalaf

Aboussekhra

2012

AGE

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Survivin, an important anti-apoptotic protein, is highly expressed in most cancers, which generally arise in cells of older individuals. We have shown here accumulation of survivin and phospho-survivin in aged normal human skin fibroblasts and mice organs. This age-related accumulation of survivin was due to protein stabilization through association with the molecular chaperone Hsp90 protein, which was also up-regulated during aging. Interestingly, Hsp90 binds preferentially to phospho-survivin, which explains its higher stability. In addition, we provide clear evidence that aged cells exhibit apoptosis resistance when challenged with UV light, cisplatin, γ-rays or H 2 O 2 as compared to their younger counterparts. In response to γ-rays and H 2 O 2 , the levels of Bcl-2 and both forms of survivin were upregulated in old cells, but not in their corresponding young ones. This repression of survivin and phosphosurvivin in young cells is p53 dependent. Importantly, survivin inhibition/down-regulation with flavopiridol or specific shRNAs increased the apoptotic response of old fibroblasts to various genotoxic agents, and restored the pro-apoptotic Bax/Bcl2 ratio and the increase in the levels of cleaved caspase-3 and PARP in old cells. These results show the role of survivin in the age-dependent resistance of human fibroblasts, and provide new insights into the molecular mechanisms that underlie the complex relationship between aging, apoptosis, and cancer.

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Section: Discussionsupporting

confidence: 93%

Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress

Al‐Khalaf

Aboussekhra

2012

AGE

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“…In a previous study, we found that caspase-3 and PARP cleavages did not occur in H 2 O 2 -induced apoptosis of both young and senescent HDFs. 1 Dysregulation of phospho-CREB in the senescent HDFs. CREB, a Bcl-2 transcription factor, plays a critical role in regulation of apoptosis in many cell types.…”

Section: Resultsmentioning

confidence: 99%

“…The senescent phenotype is characterized by an increase in cell size, a distinct flat and enlarged morphology, 1,2 appearance of senescence-associated b-galactosidase (SA-bgalactosidase) activity, 3 hypo-responsiveness to growth factors, 4 resistance to apoptosis caused by stimuli such as UV, H 2 O 2 , staurosporine, etoposide and ceramide, 1,5,6 and broad changes in gene expression. 7 The mechanisms conferring resistance to stress-induced apoptosis in senescent human diploid fibroblasts have not been well studied.…”

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confidence: 99%

Failure of stress-induced downregulation of Bcl-2 contributes to apoptosis resistance in senescent human diploid fibroblasts

Ryu

Park

2007

Cell Death Differ

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We previously reported that senescent human diploid fibroblasts (HDFs) are resistant to apoptosis induced by H 2 O 2 and staurosporine. We report here that senescent HDFs are resistant to thapsigargin-induced apoptosis as well. These agonists caused the reductions in mitochondrial membrane potential (MMP) and in the apoptosis inhibitory protein (B-cell lymphoma) only in young HDFs but not in senescent HDFs. In addition, downregulation of Bcl-2 increased the sensitivity of senescent HDFs to apoptosis induction, suggesting the significant role of Bcl-2 in apoptosis resistance of the senescent HDFs. We further found that P-cAMP response element-binding protein (CREB), a positive regulator of Bcl-2, decreased in stress-induced apoptosis of young HDFs but not in senescent HDFs, and that Bcl-2 was markedly reduced in CREB small interfering RNA (siRNA), transfected senescent HDFs. In addition, activity of protein phosphatase 2A (PP2A), which dephosphorylates p-CREB, significantly increased in young HDFs but not in senescent HDFs treated with H 2 O 2 , staurosporine or thapsigargin. Taken together, these results suggest that failure of stress-induced downregulation of Bcl-2 underlies resistance of senescent HDFs to apoptosis.

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“…Silencing FAK expression with small interfering RNAs resulted in decreased migration of lung cancer cells (28) and glioblastoma cells (29). Finally FAK silencing has been shown to lead to apoptosis in human fibroblasts (30) and ovarian cancer cells (31).…”

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confidence: 99%

N-MYC Regulates Focal Adhesion Kinase Expression in Human Neuroblastoma

Beierle

Trujillo

Nagaram

et al. 2007

Journal of Biological Chemistry

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N-MYC is a transcription factor important for the control of cellular differentiation and proliferation (1, 2). It is normally expressed in the brain and peripheral nervous system (1). N-MYC has been shown to influence the differentiation of neural crest cells. Early in mouse embryogenesis, N-MYC is present primarily in the migrating neural crest cells, but as the embryo matures, the expression of N-MYC becomes limited to those cells that are undergoing neuronal differentiation (3). Abnormal expression of N-MYC is most notably associated with the pediatric tumor of neural crest origin, neuroblastoma. Amplification of the N-MYC oncogene is the primary adverse prognostic indicator in human neuroblastoma (4, 5). The level of N-MYC expression has been shown to correlate with the growth (6 -9) and invasiveness (10) of neuroblastoma cells, and transgenic mice with N-MYC overexpression develop spontaneous neuroblastoma tumors (11). In addition, down-regulation of N-MYC with antisense oligonucleotides leads to decreases in both cellular proliferation and in anchorageindependent growth in the neuroblastoma cells (6, 9). Despite this information, the exact function and transcriptional gene targets of N-MYC in neuroblastoma are currently not well characterized (5).Focal adhesion kinase (FAK) 3 is a nonreceptor cytoplasmic 125-kDa protein-tyrosine kinase. Initial studies revealed that both the transcription of FAK mRNA (12) and the expression of FAK protein (13-19) are significantly increased in primary and metastatic breast, colon, and thyroid tumors compared with normal tissues and that these changes occur early in tumorigenesis. Real time PCR analysis of colorectal carcinoma and liver metastasis with matched normal colonic tissues demonstrated increased FAK mRNA abundance in the tumors and metastatic tissues compared with control tissues (20), suggesting that the increased FAK expression in human tumors occurs at the level of transcription. Recently the FAK promoter was cloned and characterized, and transcriptional regulation of the FAK promoter has been demonstrated (21).FAK controls a number of cell signaling pathways including proliferation, viability, motility, and survival (22-25). The inhibition of FAK with antisense oligonucleotides has been shown to cause decreased growth in tumor cells (26). In addition, FAK inhibition with a dominant-negative FAK protein (FAK-CD) inhibited cell growth in human melanoma cells (12) and in * The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Role of Src-specific phosphorylation site on focal adhesion kinase for senescence-associated apoptosis resistance

Cited by 35 publications

References 38 publications

Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress

Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress

Failure of stress-induced downregulation of Bcl-2 contributes to apoptosis resistance in senescent human diploid fibroblasts

N-MYC Regulates Focal Adhesion Kinase Expression in Human Neuroblastoma

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