P18Ink4c, but Not P27Kip1, Collaborates with Men1 to Suppress Neuroendocrine Organ Tumors

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2006 Dec 6

PMID 17145768

Citations 27

Authors

Feng Bai

Xin-Hai Pei

Toru Nishikawa

Matthew D Smith

Yue Xiong

Affiliations

Soon will be listed here.

Abstract

Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18(Ink4c) and p27(Kip1) develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice. Compared with their corresponding single mutant littermates, the p18(-/-); Men1(+/-) mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and pancreatic islets, phosphorylation of the retinoblastoma (Rb) protein at both CDK2 and CDK4/6 sites was increased in p18(-/-) and Men1(+/-) cells and was further increased in p18(-/-); Men1(+/-) cells. The remaining wild-type Men1 allele was lost in most tumors from Men1(+/-) mice but was retained in most tumors from p18(-/-); Men1(+/-) mice. Combined mutations of p27(-/-) and Men1(+/-), in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth. These results demonstrate that functional collaboration exists between p18 and Men1 and suggest that Men1 may regulate additional factor(s) that interact with p18 and p27 differently.

Citing Articles

p18INK4C and BRCA1 inhibit follicular cell proliferation and dedifferentiation in thyroid cancer.

Bai F, Liu X, Zhang X, Mao Z, Wen H, Ma J Cell Cycle. 2023; 22(13):1637-1653.

PMID: 37345432 PMC: 10361144. DOI: 10.1080/15384101.2023.2225938.

Molecular and Clinical Spectrum of Primary Hyperparathyroidism.

Jha S, Simonds W Endocr Rev. 2023; 44(5):779-818.

PMID: 36961765 PMC: 10502601. DOI: 10.1210/endrev/bnad009.

Genomic Profiling Reveals the Variant Landscape of Sporadic Parathyroid Adenomas in Chinese Population.

Tao X, Xu T, Lin X, Xu S, Fan Y, Guo B J Clin Endocrinol Metab. 2023; 108(7):1768-1775.

PMID: 36611251 PMC: 10271222. DOI: 10.1210/clinem/dgad002.

The kinome, cyclins and cyclin-dependent kinases of pituitary adenomas, a look into the gene expression profile among tumors from different lineages.

Taniguchi-Ponciano K, Portocarrero-Ortiz L, Guinto G, Moreno-Jimenez S, Gomez-Apo E, Chavez-Macias L BMC Med Genomics. 2022; 15(1):52.

PMID: 35260162 PMC: 8905767. DOI: 10.1186/s12920-022-01206-y.

Multiple Endocrine Neoplasia Type 1: Latest Insights.

Brandi M, Agarwal S, Perrier N, Lines K, Valk G, Thakker R Endocr Rev. 2020; 42(2):133-170.

PMID: 33249439 PMC: 7958143. DOI: 10.1210/endrev/bnaa031.

References

Hughes C, Rozenblatt-Rosen O, Milne T, Copeland T, Levine S, Lee J . Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell. 2004; 13(4):587-97. DOI: 10.1016/s1097-2765(04)00081-4. View

Bertolino P, Tong W, Galendo D, Wang Z, Zhang C . Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Mol Endocrinol. 2003; 17(9):1880-92. DOI: 10.1210/me.2003-0154. View

Buchwald P, Akerstrom G, Westin G . Reduced p18INK4c, p21CIP1/WAF1 and p27KIP1 mRNA levels in tumours of primary and secondary hyperparathyroidism. Clin Endocrinol (Oxf). 2004; 60(3):389-93. DOI: 10.1111/j.1365-2265.2004.01995.x. View

Yokoyama A, Wang Z, Wysocka J, Sanyal M, Aufiero D, Kitabayashi I . Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol. 2004; 24(13):5639-49. PMC: 480881. DOI: 10.1128/MCB.24.13.5639-5649.2004. View

Pei X, Bai F, Tsutsui T, Kiyokawa H, Xiong Y . Genetic evidence for functional dependency of p18Ink4c on Cdk4. Mol Cell Biol. 2004; 24(15):6653-64. PMC: 444851. DOI: 10.1128/MCB.24.15.6653-6664.2004. View

Morishita A, Masaki T, Yoshiji H, Nakai S, Ogi T, Miyauchi Y . Reduced expression of cell cycle regulator p18(INK4C) in human hepatocellular carcinoma. Hepatology. 2004; 40(3):677-86. DOI: 10.1002/hep.20337. View

Spiegel A . Focus on hereditary endocrine neoplasia. Cancer Cell. 2004; 6(4):327-32. DOI: 10.1016/j.ccr.2004.09.023. View

Lee E, Chang C, Hu N, Wang Y, Lai C, Herrup K . Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature. 1992; 359(6393):288-94. DOI: 10.1038/359288a0. View

Jacks T, Fazeli A, Schmitt E, Bronson R, Goodell M, Weinberg R . Effects of an Rb mutation in the mouse. Nature. 1992; 359(6393):295-300. DOI: 10.1038/359295a0. View

10.

Maandag E, van der Valk M, Vlaar M, Feltkamp C, OBrien J, van Roon M . Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. EMBO J. 1994; 13(18):4260-8. PMC: 395353. DOI: 10.1002/j.1460-2075.1994.tb06746.x. View

11.

Williams B, Remington L, Albert D, Mukai S, Bronson R, Jacks T . Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet. 1994; 7(4):480-4. DOI: 10.1038/ng0894-480. View

12.

Harvey M, Vogel H, Lee E, Bradley A, Donehower L . Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Res. 1995; 55(5):1146-51. View

13.

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

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

17.

Sherr C . Cancer cell cycles. Science. 1996; 274(5293):1672-7. DOI: 10.1126/science.274.5293.1672. View

18.

Kitagawa M, Higashi H, Jung H, Suzuki-Takahashi I, Ikeda M, Tamai K . The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J. 1996; 15(24):7060-9. PMC: 452531. View

19.

Zarkowska T, U S, Harlow E, Mittnacht S . Monoclonal antibodies specific for underphosphorylated retinoblastoma protein identify a cell cycle regulated phosphorylation site targeted by CDKs. Oncogene. 1997; 14(2):249-54. DOI: 10.1038/sj.onc.1200824. View

20.

Chandrasekharappa S, Guru S, Manickam P, Olufemi S, Collins F, Emmert-Buck M . Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997; 276(5311):404-7. DOI: 10.1126/science.276.5311.404. View