Deletion of the P27Kip1 Gene Restores Normal Development in Cyclin D1-deficient Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2001 Jan 3

PMID 11134518

Citations 55

Authors

Y Geng

Q Yu

E Sicinska

M Das

R T Bronson

P Sicinski

Affiliations

Soon will be listed here.

Abstract

D-type cyclins (cyclins D1, D2, and D3) are key components of cell cycle machinery in mammalian cells. These proteins are believed to drive cell cycle progression by associating with their kinase partners, cyclin-dependent kinases, and by directing phosphorylation of critical cellular substrates. In addition, D-cyclins play a kinase-independent role by sequestering cell cycle inhibitors p27(Kip1) and p21(Cip1). In the past, we and others generated cyclin D1-deficient mice and have shown that these mice display developmental abnormalities, hypoplastic retinas, and pregnancy-insensitive mammary glands. To test the significance of cyclin D1-p27(Kip1) interaction within a living mouse, we crossed cyclin D1-deficient mice with mice lacking p27(Kip1), and we generated double-mutant cyclin D1(-/-)p27(-/-) animals. Here we report that ablation of p27(Kip1) restores essentially normal development in cyclin D1-deficient mice. Our results provide genetic evidence that p27(Kip1) functions downstream of cyclin D1.

Citing Articles

PR55α-controlled protein phosphatase 2A inhibits p16 expression and blocks cellular senescence induction by γ-irradiation.

Palanivel C, Madduri L, Hein A, Jenkins C, Graff B, Camero A Aging (Albany NY). 2024; 16(5):4116-4137.

PMID: 38441530 PMC: 10968692. DOI: 10.18632/aging.205619.

CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors.

Wang J, Calizo A, Zhang L, Pino J, Lyu Y, Pollard K Sci Adv. 2023; 9(47):eadg8876.

PMID: 38000020 PMC: 10672174. DOI: 10.1126/sciadv.adg8876.

Quantitative Approaches to Study Retinal Neurogenesis.

Perez-Dones D, Ledesma-Terron M, Miguez D Biomedicines. 2021; 9(9).

PMID: 34572408 PMC: 8471905. DOI: 10.3390/biomedicines9091222.

Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin.

Xu C, Shen W, Reece E, Hasuwa H, Harman C, Kaushal S Sci Adv. 2021; 7(27).

PMID: 34193422 PMC: 8245044. DOI: 10.1126/sciadv.abf5089.

The Polycomb group protein MEDEA controls cell proliferation and embryonic patterning in Arabidopsis.

Simonini S, Bemer M, Bencivenga S, Gagliardini V, Pires N, Desvoyes B Dev Cell. 2021; 56(13):1945-1960.e7.

PMID: 34192526 PMC: 8279741. DOI: 10.1016/j.devcel.2021.06.004.

References

Fero M, Rivkin M, Tasch M, Porter P, Carow C, Firpo E . A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell. 1996; 85(5):733-44. DOI: 10.1016/s0092-8674(00)81239-8. View

Motokura T, Bloom T, Kim H, Juppner H, Ruderman J, Kronenberg H . A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991; 350(6318):512-5. DOI: 10.1038/350512a0. View

LaBaer J, Garrett M, Stevenson L, Slingerland J, Sandhu C, Chou H . New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997; 11(7):847-62. DOI: 10.1101/gad.11.7.847. View

Lukas J, Herzinger T, Hansen K, Moroni M, Resnitzky D, Helin K . Cyclin E-induced S phase without activation of the pRb/E2F pathway. Genes Dev. 1997; 11(11):1479-92. DOI: 10.1101/gad.11.11.1479. View

Leng X, Goodrich D, Harper J . S-Phase entry upon ectopic expression of G1 cyclin-dependent kinases in the absence of retinoblastoma protein phosphorylation. Curr Biol. 1997; 7(9):709-12. DOI: 10.1016/s0960-9822(06)00301-0. View

Zhang H, Hannon G, Beach D . p21-containing cyclin kinases exist in both active and inactive states. Genes Dev. 1994; 8(15):1750-8. DOI: 10.1101/gad.8.15.1750. View

Bartkova J, Lukas J, Strauss M, Bartek J . Cyclin D1 oncoprotein aberrantly accumulates in malignancies of diverse histogenesis. Oncogene. 1995; 10(4):775-8. View

Dickson C, Fantl V, Gillett C, Brookes S, Bartek J, Smith R . Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer Lett. 1995; 90(1):43-50. DOI: 10.1016/0304-3835(94)03676-a. View

Weinberg R . The retinoblastoma protein and cell cycle control. Cell. 1995; 81(3):323-30. DOI: 10.1016/0092-8674(95)90385-2. View

10.

Sherr C . D-type cyclins. Trends Biochem Sci. 1995; 20(5):187-90. DOI: 10.1016/s0968-0004(00)89005-2. View

11.

Sicinski P, Donaher J, Parker S, Li T, Fazeli A, Gardner H . Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell. 1995; 82(4):621-30. DOI: 10.1016/0092-8674(95)90034-9. View

12.

Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C . Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 1995; 9(19):2364-72. DOI: 10.1101/gad.9.19.2364. View

13.

Merino M, Manrow R, Lawrence J, Bluth R, Wittenbel K, Simpson J . Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nat Med. 1995; 1(12):1257-60. DOI: 10.1038/nm1295-1257. View

14.

Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, HORII I . Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 1996; 85(5):707-20. DOI: 10.1016/s0092-8674(00)81237-4. View

15.

Kiyokawa H, Kineman R, Soares V, HOFFMAN E, Ono M, Khanam D . Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell. 1996; 85(5):721-32. DOI: 10.1016/s0092-8674(00)81238-6. View

16.

Alevizopoulos K, Vlach J, Hennecke S, Amati B . Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. EMBO J. 1997; 16(17):5322-33. PMC: 1170164. DOI: 10.1093/emboj/16.17.5322. View

17.

Robinson G, Johnson P, Hennighausen L, Sterneck E . The C/EBPbeta transcription factor regulates epithelial cell proliferation and differentiation in the mammary gland. Genes Dev. 1998; 12(12):1907-16. PMC: 316915. DOI: 10.1101/gad.12.12.1907. View

18.

Tong W, Kiyokawa H, Soos T, Park M, Soares V, Manova K . The absence of p27Kip1, an inhibitor of G1 cyclin-dependent kinases, uncouples differentiation and growth arrest during the granulosa->luteal transition. Cell Growth Differ. 1998; 9(9):787-94. View

19.

Zhang P, Wong C, DePinho R, Harper J, Elledge S . Cooperation between the Cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development. Genes Dev. 1998; 12(20):3162-7. PMC: 317217. DOI: 10.1101/gad.12.20.3162. View

20.

Cheng M, Olivier P, Diehl J, Fero M, Roussel M, Roberts J . The p21(Cip1) and p27(Kip1) CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J. 1999; 18(6):1571-83. PMC: 1171245. DOI: 10.1093/emboj/18.6.1571. View