Effect of UCN-01, a selective inhibitor of protein kinase C, on the cell-cycle distribution of human epidermoid carcinoma, A431 cells

Akinaga, Shiro; Nomura, Kayo; Gomi, Katsushige; Okabe, Masami

doi:10.1007/bf00685899

Cited by 79 publications

(36 citation statements)

References 21 publications

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“…Among cPKC isozymes, cPKCc~, which is expressed ubiquitously in a variety of cells and tissues, is inhibited by UCN-01 most effectively, suggesting that cPKC~ is a potential candidate for the physiological target of UCN-01. The ICs0 values for growth inhibition of tumor cell lines by UCN-01, however, are 20 300 nM [3,4], and 0.15 1.56 /,tM UCN-01 is required to arrest the cell cycle of tumor cell lines [4,6]. Therefore, nPKC isozymes as well as cPKC isozymes may play a role in the anti-tumor action of UCN-01 in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

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UCN‐01, an anti‐tumor drug, is a selective inhibitor of the conventional PKC subfamily

et al. 1995

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A selective PKC inhibitor, UCN-01, was shown to exhibit anti-tumor activity in vitro and in vivo. We investigated UCN-01 with respect to isozyme-spccific PKC inhibition using purified recombinant or rabbit brain PKC isozymes, cPKCa, /3 and y, nPKC~, E and ~/, and aPKC~. Of the PKC isozymes examined, cPKCa was inhibited by UCN-01 most effectively (K~ = 0.44 nM), suggesting cPKCc~ is the prime candidate for the physiological target of UCN-01. The K~ values of UCN-01 estimated from Dixon plots for cPKC isozymes are approximately 1 nM, whereas the K i values for nPKC isozymes are about 20 nM. Moreover, the Ki value for aPKC~ is 3.8 btM. Thus, UCN-01 discriminates between PKC subfamilies. In addition, the inhibitory effects of staurosporine, H7, and calphostin C on aPKC~ were examined and compared with those for cPKCw.

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Section: Discussionmentioning

confidence: 99%

“…Both inhibitors show variable cellular effects, inhibition of proliferation of several tumor cell lines, and arrest of the cell cycle [3][4][5][6]. UCN-01, however, exhibits in vivo anti-tumor effects against human tumor xenografts and murine tumors, while staurosporine has little activity against any tumor models [3].…”

Section: Introductionmentioning

confidence: 99%

UCN‐01, an anti‐tumor drug, is a selective inhibitor of the conventional PKC subfamily

et al. 1995

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“…UCN-01 (7-hydroxystaurosporine; see Figure 1) is a staurosporine analog that initially showed higher speci®city against several PKC isoenzymes, particularly against the Ca 2+ -dependent protein kinase C (cPKCs) with an IC 50 *30 nM, with lower potency against the novel Ca 2+ -independent PKC's (nPKC's) (IC 50 *500 nM) and no e ect against the atypical PKC's (Seynaeve et al, 1994;Takahashi et al, 1987Takahashi et al, , 1989. In addition to the e ects on PKC, UCN-01 shows prominent antiproliferative e ects in several human tumor cell lines (Akinaga et al, 1991(Akinaga et al, , 1994Akiyama et al, 1997;Seynaeve et al, 1993;Wang et al, 1995). In contrast, another highly selective potent PKC inhibitor, GF 109203X shows no antiproliferative e ect despite similar capacity to inhibit PKC in vitro (Wang et al, 1995) allowing the conclusion that UCN-01's antiproliferative e ect is probably not explained solely by inhibition of PKC.…”

Section: Ucn-01mentioning

confidence: 99%

Small molecule modulators of cyclin-dependent kinases for cancer therapy

Senderowicz

2000

Oncogene

111

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“…Inhibition of the cell cycle at the G2/M phase was exhibited also by several staurosporine analogs, which are more selective PKC inhibitors, and by other structurally distinct selective PKC inhibitors [49, 501. Preferential G I accumulation was induced by a staurosporine-derived, specific PKC inhibitor (UCN-01) in A431 cells [51]. Interestingly, G1 arrest by staurosporine depend on a functional Rb protein [52].…”

Section: Pkc Acts During G1 Progression and The G 2 M Transition In Mmentioning

confidence: 99%

Linking Protein Kinase C to Cell‐Cycle Control

Livneh

Fishman

1997

European Journal of Biochemistry

199

114

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Protein kinase C (PKC) isoenzymes are involved in diverse cellular functions, including differentiation, growth control, tumor promotion, and cell death. In recent years, evidence has began to emerge suggesting a role for PKC in cell cycle control. A paper published recently, demonstrating a functional link between PKC and cell cycle control in yeast (Marini, N. J., Meldrum, E., Buehrer, B., Hubberstey, A. V., Stone, D. E., Traynor-Kaplan, A. & Reed, S. I. (1996) EMBO J. 15, 3040-3052), strengthens this data. Thus, the existence of cell-cycle-regulated pathways involving PKC in both yeast and mammals indicate that PKC may be a conserved regulator of cell cycle events that links signal transduction pathways and the cell-cycle machinery. In this paper, we will review current data on the cell cycle components that are targets for PKC regulation.PKC enzymes appear to operate as regulators of the cell cycle at two sites, during G1 progression and G 2 M transition. In G1, the overall effect of PKC activation is inhibition of the cell cycle at mid to late G1. This cell cycle inhibition correlates with a blockage in the normal phosphorylation of the tumor suppressor retinoblastoma Rb protein, presumably through an indirect mechanism. The reduced activity of the cyclin-dependent kinase, Cdk2, appears to be the major effect of PKC activation in various cell systems. This may also underlie the inhibition of Rb phosphorylation exhibited by PKC activation. Several mechanisms were described in different studieq on the regulation of Cdk2 activity by PKC; reduced Cdk-activating kinase activity, diminished expression of the Cdk2 partners cyclins E or A, and the increased expression of the cyclin-dependent inhibitors, p2lWAF1 and p27K'P', which are capable of binding to cyclidCdk2 complexes.PKC enzymes were also shown to play a role in G2/M transition. Among the suggested mechanisms is suppression of Cdc2 activity. However, most of the published data strongly implicate PKC in lamin B phosphorylation and nuclear envelope disassembly.Keywords: protein kinase C ; cell cycle; cyclin ; cyclin-dependent kinase; Cdk inhibitor; retinoblastoma protein; p53 protein; phorbol ester; GUS transition; G2/M transition. Protein kinase C and growth regulationThe term protein kinase C (PKC) stands for a group of at least ten serinehhreonine kinases that are characterized by a high degree of similarity in their catalytic kinase domains and cysteine-rich regions [l-41. The PKC family is subdivided into three groups; the classical PKC members (a, p, y) are Ca2+ and diacylglycerol-dependent, the novel PKCs (6, E , q and d) are Ca2+-independent but diacylglycerol-dependent and the atypical PKCs ([ and 2) are not activated by Ca*+ and diacylglycerol in vitro [3, 41. This may account for the multiplicity and diversity of the cellular activities implicated to be mediated by PKC, sinceCorrespondence to

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Effect of UCN-01, a selective inhibitor of protein kinase C, on the cell-cycle distribution of human epidermoid carcinoma, A431 cells

Cited by 79 publications

References 21 publications

UCN‐01, an anti‐tumor drug, is a selective inhibitor of the conventional PKC subfamily

UCN‐01, an anti‐tumor drug, is a selective inhibitor of the conventional PKC subfamily

Small molecule modulators of cyclin-dependent kinases for cancer therapy

Linking Protein Kinase C to Cell‐Cycle Control

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