Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-β1-induced apoptosis in human gastric cancer cells

Kim, Sang Gyun; Kim, Se Nyun; Jong, Hyun Soon; Kim, Noe Kyeong; Hong, Samin; Kim, Seong‐Jin; Bang, Yung Jue

doi:10.1038/sj.onc.1204203

Cited by 51 publications

(48 citation statements)

References 40 publications

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“…Stimulation and inhibition of expression of proand anti-apoptotic Bcl family members, respectively, with subsequent caspase activation has been implicated in TGF-b-induced apoptosis (Fig. 3) (Motyl et al, 1998;Francis et al, 2000;Chipuk et al, 2001;Kim et al, 2001). In addition, TGF-b-mediated induction of Id3 expression in primary B lymphocyte progenitors (Kee et al, 2001), TIEG in mink lung epithelial and Hep3B cells (Chalaux et al, 1999;Ribeiro et al, 1999), and TGFb-stimulated clone 22 (TSC-22) in gastric carcinoma cells (Ohta et al, 1997), have been implicated in apoptosis.…”

Section: Regulation Of Apoptosis By Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

399

278

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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Section: Regulation Of Apoptosis By Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

399

278

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“…Inhibition of CDKs, as opposed to activation of CDKs as discussed previously (21,30,31,(33)(34)(35), has been shown by others to be cytotoxic in various models including colorectal carcinoma cells (45,46). The finding that potentiation is evident in p21…”

Section: Expression Of P21mentioning

confidence: 99%

“…Cip1 (14,29,30,32) and its CDK substrates (21,30,31,(33)(34)(35) appear to be able to promote apoptosis, with or without concomitant chemotherapeutic …”

Section: Studies Have Demonstrated Increased Sensitivity Of P21mentioning

confidence: 99%

P21Cip1 Is a Critical Mediator of the Cytotoxic Action of Thymidylate Synthase Inhibitors in Colorectal Carcinoma Cells

et al. 2004

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We have demonstrated previously that interferon (IFN)-␥ sensitizes human colon carcinoma cell lines to the cytotoxic effects of 5-fluorouracil combined with leucovorin and to the thymidylate synthase inhibitor, ZD9331, dependent on thymineless stress-induced DNA damage, independent of p53. Here we demonstrate that the cyclin-dependent kinase (CDK) inhibitor p21Cip1 regulates thymineless stress-induced cytotoxicity in these cells. HCT116 wild-type (wt) and p53؊/؊ cells underwent apoptosis and loss in clonogenic survival when exposed to ZD9331, whereas p21Cip1 ؊/؊ cells were resistant. Cip1 ؊/؊ cells accumulated in S phase within 24 h of ZD9331 exposure; however, wt cells exited S-phase more rapidly, where apoptosis occurred before mitosis, either in late S or G 2 . Finally, the CDK inhibitor roscovitine potentiated the cytotoxic activity of ZD9331 in both wt and p21Cip1 ؊/؊ cells, strongly suggesting a role for p21Cip1 -dependent CDK inhibition in cytotoxicity induced by thymidylate synthase inhibition. In summary, p21Cip1 positively regulates the cytotoxic action of thymidylate synthase inhibitors, negatively regulates the cytotoxic action of IFN-␥, and enhances S-phase exit after thymineless stress, possibly via interaction with CDK-cyclin complexes.

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“…Previous reports have shown that caspasemediated cleavage permits the release of the cyclin/Cdk complex from the p21 WAF1/CIP1 inhibitor, resulting in an elevation of cyclin/Cdk kinase activity in the early stages of apoptosis (22). The up-regulation of cyclin/Cdk kinase activity is required for apoptotic progression in several cell types, including HU-VEC cells, SK-HEP-1 cells, and HeLa cells (22,23). Therefore, we speculated that p21 WAF1/CIP1 plays a pivotal role in the induction of apoptosis.…”

mentioning

confidence: 99%

The c-Jun N-terminal Kinase 1 Activity Is Differentially Regulated by Specific Mechanisms during Apoptosis

Ham

Choi

Chun

et al. 2003

Journal of Biological Chemistry

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We show here that JNK1 activity is rapidly up-regulated and prolonged by specific mechanisms during apoptosis induced by paclitaxel-or ginsenoside-Rh2 in SK-HEP-1 cells. The early phase of JNK1 activation is prevented in cells expressing the dominant negative SEK1 mutant, although this JNK1 perturbation does not prevent apoptotic cell death. The later phase of JNK1 activation, which is temporally coincided with caspasedependent cleavage of JNK1-associated p21 WAF1/CIP1 , is efficiently prevented by expressing p21D112N, an uncleavable mutant of p21 WAF1/CIP1 and this perturbation of JNK1 activation results in prevention of apoptosis. The later JNK1 activation and apoptotic progression are also prevented by co-treatments of cells with rottlerin, a PKC-␦ inhibitor or z-VAD-fmk, a pan caspase inhibitor. We also provide evidence that apoptotic cell death is significantly promoted in cells expressing JNK1, while this apoptotic cell death is effectively suppressed in cells expressing the dominant negative JNK1 mutant (DN-JNK1) or JBD, a JNK inhibitor protein. Thus, the later phase of JNK1 activation, which is linked to a caspase-dependent mechanism that requires PKC-␦ activity, is associated with the induction of apoptosis, while the early JNK1 activation that is associated with a SEK1-mediated mechanism is not directly involved in apoptotic progression.

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Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-β1-induced apoptosis in human gastric cancer cells

Cited by 51 publications

References 40 publications

Regulation of cell proliferation by Smad proteins

Regulation of cell proliferation by Smad proteins

P21Cip1 Is a Critical Mediator of the Cytotoxic Action of Thymidylate Synthase Inhibitors in Colorectal Carcinoma Cells

The c-Jun N-terminal Kinase 1 Activity Is Differentially Regulated by Specific Mechanisms during Apoptosis

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