DOI: 10.1101/gad.11.4.492. The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2.

The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2.

10.1101/gad.11.4.492

Crossref journal-article

Cold Spring Harbor Laboratory

Genes & Development (246)

Abstract

In dividing cells, p27(Kip1) is predominantly bound to cyclin D-cdk4 without inhibiting this kinase. Upon being induced by TGF-beta or with a conditional expression system in lung epithelial cells, p15(Ink4b) binds to and inhibits the cyclin D-dependent kinases, prevents p27 binding to these cdk complexes, and promotes p27 binding and inhibition of cyclin-cdk2. In vitro, however, p15 prevents p27 binding only if it has access to cyclin D-cdk4 first. We present evidence that the different subcellular location of p15 and p27 ensures the prior access of p15 to cdk4. In the cell, p15 is localized mostly in the cytoplasm, whereas p27 is nuclear. p15 prevails over p27 or a p27 construct consisting of the cdk inhibitory domain tagged with a nuclear localization signal. However, when p15 and p27 are forced to reside in the same subcellular location, either the cytoplasm or the nucleus, p15 no longer prevents p27 from binding to cdk4. These properties allow p15 and p27 to coordinately inhibit cdk4 and cdk2.

Bibliography

ReynisdÃ³ttir, I., & MassaguÃ©, J. (1997). The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes & Development, 11(4), 492â503.

Authors 2

I Reynisdóttir (first)
J Massagué (additional)

References 51 Referenced 262

10.1016/0092-8674(93)90488-C
10.1101/gad.7.5.812
{'key': '2021111418430243000_11.4.492.3', 'first-page': '1633', 'article-title': 'Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein.', 'volume': '9', 'year': '1994', 'journal-title': 'Oncogene'} / Oncogene / Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein. (1994)
{'key': '2021111418430243000_11.4.492.4', 'first-page': '1283', 'article-title': 'Cyclin E/Cdk2 activity is controlled by different mechanisms in the Go and Gl phases of the cell cycle.', 'volume': '7', 'year': '1996', 'journal-title': 'Cell Growth Differ'} / Cell Growth Differ / Cyclin E/Cdk2 activity is controlled by different mechanisms in the Go and Gl phases of the cell cycle. (1996)
{'key': '2021111418430243000_11.4.492.5', 'first-page': '3810', 'article-title': 'Type I receptors specify growth inhibitory and transcripitonal responses to TGF-β and activin.', 'volume': '14', 'year': '1994', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Type I receptors specify growth inhibitory and transcripitonal responses to TGF-β and activin. (1994)
10.1091/mbc.3.5.571
10.1016/0092-8674(93)90500-P
{'key': '2021111418430243000_11.4.492.8', 'first-page': '1169', 'article-title': 'WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.', 'volume': '54', 'year': '1994', 'journal-title': 'Cancer Res.'} / Cancer Res. / WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. (1994)
10.1126/science.274.5287.499
10.1073/pnas.89.12.5547
10.1101/gad.8.24.2939
10.1126/science.7863327
10.1016/S0065-230X(08)60352-8
10.1038/371257a0
10.1128/MCB.16.3.859 / Mol. Cell. Biol. / Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. (1996)
Harlow, E. and D. Lane. Antibodies: A laboratory handbook. 1988. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
10.1016/0092-8674(93)80048-J
10.1073/pnas.91.12.5490
10.1126/science.271.5257.1861
10.1073/pnas.91.12.5291
10.1128/MCB.15.5.2672 / Mol. Cell. Biol. / Novel INK4 proteins, pl9 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. (1995)
10.1038/376313a0
10.1016/0092-8674(94)90257-7
10.1016/0092-8674(90)90251-9
10.1101/gad.9.6.639
10.1073/pnas.93.8.3259
10.1101/gad.10.2.142
10.1038/375159a0
10.1016/0092-8674(92)90360-O
{'key': '2021111418430243000_11.4.492.30', 'first-page': '2066', 'article-title': 'D-type cyclin-dependent kinase activity in mammalian cells.', 'volume': '14', 'year': '1994', 'journal-title': 'Mol. Cell Biol.'} / Mol. Cell Biol. / D-type cyclin-dependent kinase activity in mammalian cells. (1994)
{'key': '2021111418430243000_11.4.492.31', 'first-page': '2077', 'article-title': 'Identification of G1 kinase activity for cdk6, a novel cyclin D partner.', 'volume': '14', 'year': '1994', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Identification of G1 kinase activity for cdk6, a novel cyclin D partner. (1994)
10.1006/excr.1994.1063
10.1038/372570a0
10.1126/science.7863329
10.1002/j.1460-2075.1995.tb07026.x / EMBO J. / Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. (1995)
10.1101/gad.8.1.9
10.1016/0092-8674(94)90572-X
10.1091/mbc.6.9.1197
10.1101/gad.9.15.1831
10.1038/382325a0
10.1038/366704a0
10.1101/gad.9.10.1149
{'key': '2021111418430243000_11.4.492.43', 'first-page': '3683', 'article-title': 'A novel inhibitor of cyclin-cdk activity detected in transforming growth factor β-arrested epithelial cells.', 'volume': '14', 'year': '1994', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / A novel inhibitor of cyclin-cdk activity detected in transforming growth factor β-arrested epithelial cells. (1994)
{'key': '2021111418430243000_11.4.492.44', 'first-page': '135', 'article-title': 'Formation of p27-CDK complexes during the human mitotic cell cycle.', 'volume': '7', 'year': '1996', 'journal-title': 'Cell Growth Differ.'} / Cell Growth Differ. / Formation of p27-CDK complexes during the human mitotic cell cycle. (1996)
{'key': '2021111418430243000_11.4.492.45', 'first-page': '3389', 'article-title': 'Induction of p21 (WAF-1/CIP1) during differentiation.', 'volume': '9', 'year': '1994', 'journal-title': 'Oncogene'} / Oncogene / Induction of p21 (WAF-1/CIP1) during differentiation. (1994)
10.1101/gad.10.12.1491
10.1016/0092-8674(94)90573-8
10.1126/science.7652577
10.1016/0092-8674(91)90100-D
10.1101/gad.7.8.1572
10.1083/jcb.133.2.391

Dates

Type	When
Created	18 years, 2 months ago (June 5, 2007, 5:15 p.m.)
Deposited	3 years, 9 months ago (Nov. 14, 2021, 9:58 p.m.)
Indexed	1 month, 1 week ago (July 11, 2025, 6:24 a.m.)
Issued	28 years, 6 months ago (Feb. 15, 1997)
Published	28 years, 6 months ago (Feb. 15, 1997)
Published Online	28 years, 6 months ago (Feb. 15, 1997)
Published Print	28 years, 6 months ago (Feb. 15, 1997)

Funders 0

None

BibTeX

@article{Reynisd_ttir_1997, title={The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2.}, volume={11}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.11.4.492}, DOI={10.1101/gad.11.4.492}, number={4}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Reynisdóttir, I and Massagué, J}, year={1997}, month=feb, pages={492–503} }

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