Induction of p21CIP1/Waf1and Activation of p34cdc2Involved in Retinoic Acid-Induced Apoptosis in Human Hepatoma Hep3B Cells

Hsu, Shih-Lan; Chen, Mei‐Chih; Chou, Ya-Hui; Hwang, Guang-Yuh; Yin, Sui-Chu

doi:10.1006/excr.1999.4397

Cited by 54 publications

(43 citation statements)

References 32 publications

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“…CDK2, cyclin E, p27 and p21 in these immunoprecipitates were subjected to immunoblot analysis, and CDK2 activities were determined as described in Experimental Procedures. (Hsu et al, 1999), which is in agreement with the reported failure of cisplatin to upregulate p21 in cisplatin-resistant tumour cells (Mujoo et al, 2003(Mujoo et al, , 2005. In contrast, several reports have provided evidence that p21 protects cells from apoptosis (Gartel and Tyner, 2002;Liu et al, 2003), and this makes it likely that cell context and the cellular signalling pathway induced by the specific chemotherapeutic drug determine whether p21 facilitates or antagonises apoptosis.…”

Section: Discussionsupporting

confidence: 82%

Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21

Kuang

Huang

et al. 2006

Br J Cancer

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The cisplatin analogue 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinum IV (DAP) is a DNA-damaging agent that will be entering clinical trials for its potent cytotoxic effects against cisplatin-resistant tumour cells. This cytotoxicity may reside in its ability to selectively activate G1-phase checkpoint response by inhibiting CDKs via the p53/p21 pathway. We have now evaluated the role of another CDK inhibitor p27 as a contributor to DAP-mediated inhibition of G1-phase CDK2 activity. Our studies in ovarian A2780 tumour cells demonstrate that p27 levels induced by DAP are comparable to or greater than those seen for p21. The induction of p27 is not through a transcriptional mechanism, but rather is due to a four-fold increase in protein stabilisation through a mechanism dependent on p21. Moreover, DAP-induced p21 promoted the selective increase of p27 in the CDK2 complex, but not in CDK4 complex, and this selective increase contributed to inhibition of the CDK2 kinase activity. The inhibited complex contained either p27 or p21, but not both, with the relative levels of cyclin E associated with p27 and p21 indicating that about 25% of the inhibition of CDK2 activity was due to p27 and 75% due to p21. This study provides the first evidence that p27 upregulation is directly attributable to activation of the p53/p21 pathway by a DNA-damaging agent, and promulgates p53/p21/p27 axis as a significant component of checkpoint response.

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Section: Discussionsupporting

confidence: 82%

Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21

Kuang

Huang

et al. 2006

Br J Cancer

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“…This agent has potent effects against acute promyelocytic leukemia blast cells, and its introduction in the clinical management of the disease has dramatically changed the outcome of this historically fatal subtype of acute leukemia (5). RA and other retinoids have been shown to inhibit cell growth or to promote programmed cell death of neoplastic cells of diverse origin (7)(8)(9)(10)(11)(12)(13)(14). The molecular mechanisms that regulate the induction of the biological effects of retinoids include a series of signaling events that are initiated by the binding of retinoids to specific receptors in the nucleus of target cells.…”

Section: All-trans-retinoic Acid (Ra)mentioning

confidence: 99%

Activation of Protein Kinase Cδ by All-trans-retinoic Acid

Kambhampati

Verma

et al. 2003

Journal of Biological Chemistry

102

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All-trans-retinoic acid (RA) is a potent inhibitor of leukemia cell proliferation and induces differentiation of acute promyelocytic leukemia cells in vitro and in vivo.For RA to induce its biological effects in target cells, binding to specific retinoic acid nuclear receptors is required. The resulting complexes bind to RA-responsive elements (RAREs) in the promoters of RA-inducible genes to initiate gene transcription and to generate protein products that mediate the biological effects of RA. In this report, we provide evidence that a member of the protein kinase C (PKC) family of proteins, PKC␦, is activated during RA treatment of the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line. Such RA-dependent phosphorylation was also observed in primary acute promyelocytic leukemia cells and resulted in activation of the kinase domain of PKC␦. In studies aimed at understanding the functional relevance of PKC␦ in the induction of RA responses, we found that pharmacological inhibition of PKC␦ (but not of other PKC isoforms) diminished RA-dependent gene transcription via RAREs. On the other hand, overexpression of a constitutively active form of the kinase strongly enhanced RA-dependent gene transcription via RAREs. Gel shift assays and chromatin immunoprecipitation studies demonstrated that PKC␦ associated with retinoic acid receptor-␣ and was present in an RA-inducible protein complex that bound to RAREs. Pharmacological inhibition of PKC␦ activity abrogated the induction of cell differentiation and growth inhibition of NB-4 blast cells, demonstrating that its function is required for such effects. Altogether, our data provide strong evidence that PKC␦ is activated in an RA-dependent manner and plays a critical role in the generation of the biological effects of RA in malignant cells.

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“…The cdki protein p21 WAF1/CIP1 has been reported to inhibit 5 as well as to induce apoptosis. 6,7 Similarly, the chemical inhibitors of cdk activities, olomoucine and roscovitine, can induce cell death, 8 -10 display synergy with inducers of apoptosis, 7,11 but also prevent apoptosis. 5,[12][13][14] A difficulty with the interpretation of the experiments using olomoucine resides in the fact that high concentrations (100 M) of the drug are required to produce cellular effects.…”

mentioning

confidence: 99%

Cellular effects of purvalanol A: A specific inhibitor of cyclin‐dependent kinase activities

Villerbu

Gaben

Redeuilh

et al. 2001

Intl Journal of Cancer

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We have studied the effects of purvalanol A on the cell cycle progression, proliferation and viability. In synchronized cells, purvalanol A induced a reversible arrest the progression in G1 and G2 phase of the cell cycle, but did not prevent the completion of DNA synthesis in S-phase cells. The specificity of action of the drug was supported by the selective inhibition of the phosphorylation of cyclin-dependent kinase (cdk) substrates such as Rb and cyclin E. The cell contents of cyclins D1 and E were lower in cells incubated with purvalanol A compared to controls, but the level of the cdk inhibitory protein p21 WAF1/CIP1 was increased, indicating that the drug did not cause a general inhibition of gene expression. Purvalanol A did not inhibit transcription under cell-free conditions. This compound, however, caused an inhibition of the estradiol-induced expression of an integrated luciferase gene, suggesting that cdk or related enzymes may participate in the regulation of the activity of certain promoters. When exponentially growing cells, both mouse fibroblasts and human cancer cell lines, were incubated with purvalanol A for prolonged periods of time (24 hr After mitosis, cells stimulated by appropriate exogenous or internal signals will reinitiate their progression through G1 phase to the next round of DNA replication and mitosis. The same is true for quiescent cells, i.e., cells that have been deprived of mitogenic stimuli. The progression through the cell cycle requires the activity of protein kinases activated by cyclins, regulatory proteins whose expression is regulated by growth factor signaling and by the subsequent cellular mechanisms. Several of these cyclin-dependent kinases (cdk) have been documented. Cyclin D-activated kinases (cdk4 and cdk6) are active toward mid-G1, and cyclin E-activated cdk2 at the end of G1/entry into S-phase. Cyclin A-activated cdk2 is essentially active in the S-and G2-phases, whereas the cyclin B-activated cdk1 (cdc2) is necessary and sufficient to ensure mitosis. Cdk are characterized by a conserved PSTAIRE sequence, and their targets are serine and threonine residues followed by a proline. They are generally constitutively expressed, and for their activation they require specific phosphorylations/dephosphorylations of serine/threonine/tyrosine residues, besides the formation of a complex with an appropriate cyclin. 1,2 The regulation of cdk activities during the cell cycle is mediated by several mechanisms: (i) expression of the corresponding cyclin; (ii) activation of kinases (cdk-activating kinase, CAK, a cdk7/ cyclin H complex) and phosphatases needed for the phosphorylation/dephosphorylation of specific aminoacid residues; and (iii) binding to cdk inhibitory proteins (cdki), members of the families WAF1/CIP1/KIP1 (including p21 WAF1/CIP1 , p27 KIP1 , p57 KIP2 ) and INK (p16 INK4 , p15, p18). 3 Different cdk display definite specificities toward protein substrates. Both cdk4 and cdk2 phosphorylate the Rb protein but on different sites. 4 In addition, cdk2 activated by ...

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Induction of p21CIP1/Waf1and Activation of p34cdc2Involved in Retinoic Acid-Induced Apoptosis in Human Hepatoma Hep3B Cells

Cited by 54 publications

References 32 publications

Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21

Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21

Activation of Protein Kinase Cδ by All-trans-retinoic Acid

Cellular effects of purvalanol A: A specific inhibitor of cyclin‐dependent kinase activities

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