Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals

Polyák, Kornélia; Lee, Mong Hong; Erdjument‐Bromage, Hediye; Koff, Andrew; Roberts, James M.; Tempst, Paul; Massagué, Joan

doi:10.1016/0092-8674(94)90572-x

Cited by 1,997 publications

(1,420 citation statements)

References 37 publications

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“…We were unable to detect p15 INK4B in TGF-b1-treated IEC-6 cells, although we can easily detect this inhibitor in mink lung epithelial cells. We were able to detect expression of two universal Cdk inhibitors, p21 (Harper et al, 1993;El-Deiry et al, 1993;Xiong et al, 1993) and p27 (Polyak et al, 1994; Figure 2 The abundance of cyclin D1/Cdk4 complexes, Cdk4-associated kinase activity and cyclin D3/p27 in TGF-b1-treated cells. Serum-starved, quiescent IEC-6 cultures were stimulated with 5% FBS with vehicle (7) or TGF-b1 (+).…”

Section: Resultsmentioning

confidence: 98%

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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Transforming growth factor-beta 1 (TGF-b1) arrests intestinal epithelial cells (RIE-1 and IEC-6) in the G1 phase of the cell cycle and inhibits cyclin D1 expression. This report describes experiments designed to elucidate the mechanism of cyclin D1 inhibition and to determine whether inhibition of cyclin D1 expression is the cause, rather than the result, of TGF-b1-mediated cell cycle arrest. TGF-b1 inhibition of IEC-6 cell proliferation was associated with a decrease in the abundance of cyclin D1/Cdk4 complexes and a corresponding decrease in Cdk4-dependent phosphorylation of the retinoblastoma protein. Metabolic labeling studies indicated that TGFb1 inhibited cyclin D1 synthesis without altering the rate of cyclin D1 protein degradation. Cyclin D1 antisense oligonucleotides blocked serum-stimulated induction of cyclin D1 and DNA synthesis, whereas cyclin D1 sense oligonucleotides had no e ect. RIE-1 cells were engineered to overexpress human cyclin D1 under the control of a tetracycline-repressible promoter. These cells entered S phase in the presence of TGF-b1 only when human cyclin D1 was derepressed by the withdrawal of tetracycline. These data indicate that TGF-b1 inhibits the synthesis of cyclin D1 in gut epithelial cells and that this inhibition is the cause, rather than the result, of TGF-b1-mediated arrest of intestinal epithelial cell proliferation.

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Section: Resultsmentioning

confidence: 98%

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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“…A protein encoded by an alternative reading frame of INK4A, p19 ARF , is able to arrest the cell cycle, although there is no evidence that it acts as a direct CDK inhibitor (Quelle et al, 1995). The other CDK inhibitor family includes p21(Cip1/Waf1), p27 Kip1 (Polyak et al, 1994;Toyoshima and Hunter, 1994), and p57 Kip2 (Lee et al, 1995;Matsuoka et al, 1995). The archetypal member of this family, p21, was isolated as a Cdk2-associated protein and an inhibitor of Cdk2 (Gu et al, 1993;Harper et al, 1993;Xiong et al, 1993a), a gene induced by the tumor suppressor p53 (El-Deiry et al, 1993) and a gene whose RNA expression is increased in senescent cells (Noda et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells

Poon

Hunter

1998

Oncogene

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The tumor suppressor p53 and its target the CDK inhibitor p21 (Cip1/Waf1) are key components of the cellular response to DNA damage. Insight into how p21 is regulated in normal cells, and how it may be deregulated in tumor cells is important for the understanding of tumorigenesis. p21 was induced in normal human diploid ®broblasts after UV irradiationinduced DNA damage, but, at a high dose of UV irradiation, a faster mobility form of p21 on SDS ± PAGE (designated p21D) was expressed. Surprisingly, in a variety of growing transformed cell lines, the level of p21 was low but p21D was prominent. We found that p21D appeared to be derived through a loss of around 10 amino acids from the C-terminus of p21, which theoretically would remove the PCNA binding domain, a second cyclin binding domain and the nuclear localization signal sequence. Several characteristics distinguish p21 from p21D. Both the full length p21 and p21D could be stabilized by a proteasome inhibitor, but only the full length p21 was associated with Cdk2 and PCNA. Consistent with this, gel ®ltration chromatography revealed that all the full length p21 in the cell was complexed to other proteins, whereas a signi®cant portion of p21D was in monomeric form. Moreover, p21 was mainly localized to the nucleus, but p21D was mainly localized to the cytoplasm. We propose that the decrease in p21 and increase in p21D could contribute to the deregulation of the cell cycle, and could be a mechanism involved in cellular transformation.

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“…When visible reduction of radiographic signal was not obvious, densitometry was performed (Ultrascan XL laser densitometer; Pharmacia/LKB, Freiburg, Germany) to confirm our interpretation. (Polyak et al, 1994;Toyoshima and Hunter, 1994;Ponce-Castaneda et al, 1995;Pieptenol et al, 1995;Bullrich et al, 1995). As we previously reported, exon lb of the p27KiPJ gene contains a polymorphism: at codon 109, guanine is substituted for thymine (GTC to GGC), resulting in an amino acid substitution of glycine for valine (Val to Gly) .…”

Section: Microsatellite Polymorphismsmentioning

confidence: 99%

Ovarian cancer has frequent loss of heterozygosity at chromosome 12p12.3-13.1 (region of TEL and Kip1 loci) and chromosome 12q23-ter: evidence for two new tumour-suppressor genes

Hatta

Takeuchi²,

Yokota³

et al. 1997

Br J Cancer

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Summary Identification of the key genetic alterations leading to ovarian cancer is in its infancy. Polymerase chain reaction (PCR)-based analysis of loss of heterozygosity (LOH) is a powerful method for detecting regions of altered tumour-suppressor genes. Focusing on chromosome 12, we examined 23 ovarian cancer samples for LOH using 31 highly polymorphic microsatellite markers and found the chromosomal localization of two putative tumour-suppressor genes. Two commonly deleted regions were 12p12.3-13.1 in 6/23 (26%) and 12q23-ter in 7/23 (30%) samples. LOH on chromosome 12 was more common in late-stage ovarian carcinomas. The region of LOH at 1 2p12.3-13.1 includes the genes that code for the ETS-family transcriptional factor, known as TEL, and the cyclin-dependent kinase inhibitor, known as p27('Pl. Mutational analysis of both TEL and p27KiP' using single-strand conformation polymorphism (SSCP) showed no abnormalities, suggesting that the altered gene in this region is neither of these genes. Taken together, our data suggest that new tumoursuppressor genes in the region of chromosomes 12p12.3-13.1 and 12q23-ter may be involved in the development of ovarian cancer.

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Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals

Cited by 1,997 publications

References 37 publications

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells

Ovarian cancer has frequent loss of heterozygosity at chromosome 12p12.3-13.1 (region of TEL and Kip1 loci) and chromosome 12q23-ter: evidence for two new tumour-suppressor genes

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