p27Kip1: Regulation and Function of a Haploinsufficient Tumor Suppressor and Its Misregulation in Cancer

doi:10.1006/excr.2000.5143

Experimental Cell Research

Volume 264, Issue 1, 10 March 2001, Pages 148-168

https://doi.org/10.1006/excr.2000.5143 Get rights and content

Abstract

A major function of p27, also known as Kip1, is to bind and inhibit cyclin/cyclin-dependent kinase complexes, thereby blocking cell cycle progression. As p27 operates at the heart of the cell cycle, it is perhaps not surprising that it is emerging as a key player in multiple cell fate decisions including proliferation, differentiation, and cell death. The central role of p27 makes it important in a variety of disease processes that involve aberrations in cellular proliferation and other cell fates. Most notable among these processes is neoplasia. A large number of studies have reported that p27 expression is frequently downregulated in human tumors. In most tumor types, reduced p27 expression correlates with poor prognosis, making p27 a novel and powerful prognostic marker. In addition to these practical implications, murine and tissue culture models have shown that p27 is a potent tumor suppressor gene for multiple epithelially derived neoplasias. Loss of p27 cooperates with mutations in several oncogenes and tumor suppressor genes to facilitate tumor growth, indicating that p27 may be a “nodal point” for tumor suppression. In contrast to most tumor suppressor genes studied to date, which are recessive at the cellular level, p27 is haploinsufficient for tumor suppression. The fact that tumor suppression by p27 is critically dependent on the absolute level of p27 expression indicates that p27 acts as a rheostat rather than as an on/off switch to control growth and neoplasia.

References (239)

K. Polyak et al.
Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals
Cell
(1994)
H. Kobayashi et al.
Fluorescence in situ hybridization mapping of translocations and deletions involving the short arm of human chromosome 12 in malignant hematologic diseases
Blood
(1994)
R. Morosetti et al.
Alterations of the p27KIP1 gene in non-Hodgkin's lymphomas and adult T-cell leukemia/lymphoma
Blood
(1995)
X. Qian et al.
DNA methylation regulates p27kip1 expression in rodent pituitary cell lines
Am. J. Pathol.
(1998)
H. Kawana et al.
Role of p27Kip1 and cyclin-dependent kinase 2 in the proliferation of non-small cell lung cancer
Am. J. Pathol.
(1998)
R. Chiarle et al.
Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma
Blood
(2000)
M. Morimoto et al.
Modification of cullin-1 by ubiquitin-like protein Nedd8 enhances the activity of SCF(skp2) toward p27(kip1)
Biochem. Biophys. Res. Commun.
(2000)
H. Zhang et al.
p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase
Cell
(1995)
J.D. Weber et al.
Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27
J. Biol. Chem.
(1997)
W. Hu et al.
RhoA stimulates p27(Kip) degradation through its regulation of cyclin E/CDK2 activity
J. Biol. Chem.
(1999)

A. Hirai et al.

Geranylgeranylated rho small GTPase(s) are essential for the degradation of p27Kip1 and facilitate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells

J. Biol. Chem.

(1997)

J.R. Graff et al.

Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression

J. Biol. Chem.

(2000)

N. Ishida et al.

Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability

J. Biol. Chem.

(2000)

T.K. Kwon et al.

Characterization of the murine cyclin-dependent kinase inhibitor gene p27^Kip1

Gene

(1996)

S.S. Millard et al.

Enhanced ribosomal association of p27(Kip1) mRNA is a mechanism contributing to accumulation during growth arrest

J. Biol. Chem.

(1997)

S.W. Blain et al.

Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4

J. Biol. Chem.

(1997)

R. Sears et al.

Ras enhances Myc protein stability

Mol. Cell

(1999)

M.H. Glickman et al.

A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3

Cell

(1998)

K. Hofmann et al.

The PCI domain: A common theme in three multiprotein complexes

Trends Biochem. Sci.

(1998)

H.Y. Yang et al.

Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27

J Biol. Chem.

(2000)

L. Hengst et al.

A cell cycle-regulated inhibitor of cyclin-dependent kinases

Proc. Natl. Acad. Sci. USA

(1994)

C.J. Sherr et al.

Inhibitors of mammalian G1 cyclin-dependent kinases

Genes Dev.

(1995)

C.J. Sherr et al.

CDK inhibitors: Positive and negative regulators of G1-phase progression

Genes Dev.

(1999)

J. Slingerland et al.

Regulation of the cdk inhibitor p27 and its deregulation in cancer

J. Cell Physiol.

(2000)

A.A. Russo et al.

Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex [see comments]

Nature

(1996)

F. Bullrich et al.

Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27Kip1, to regions involved in human cancer

Cancer Res.

(1995)

J.A. Pietenpol et al.

Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias

Cancer Res.

(1995)

M.V. Ponce-Castaneda et al.

p27Kip1: Chromosomal mapping to 12p12–12p13.1 and absence of mutations in human tumors

Cancer Res.

(1995)

C.J. Kemp et al.

The murine Cdkn2a gene (p27/Kip1) maps to distal chromosome 6 and is excluded as Pas1

Mamm. Genome

(2000)

S. Takeuchi et al.

Allelotype analysis of childhood acute lymphoblastic leukemia

Cancer Res.

(1995)

Y. Hatta et al.

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

Br. J. Cancer

(1997)

A.S. Kibel et al.

Deletion mapping at 12p12–13 in metastatic prostate cancer

Genes Chromosomes Cancer

(1999)

N. Kawamata et al.

Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies

Cancer Res.

(1995)

K.S. Spirin et al.

p27 mutation found in breast cancer

Cancer Res.

(1996)

A.A. Ferrando et al.

Mutational analysis of the human cyclin-dependent kinase inhibitor p27kip1 in primary breast carcinomas

Hum. Genet.

(1996)

J. Tsihlias et al.

The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer

Annu. Rev. Med.

(1999)

P.A. Jones et al.

Cancer epigenetics comes of age

Nature Genet.

(1999)

J.C. Wilson et al.

The p27/Kip1 locus shows no loss of heterozygosity in human pituitary adenomas

J. Neurooncol.

(1999)

C. Catzavelos et al.

Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer [see comments]

Nature Med.

(1997)

M. Loda et al.

Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas

Nature Med.

(1997)

L. Jin et al.

Transforming growth factor-beta, transforming growth factor-beta receptor II, and p27Kip1 expression in nontumorous and neoplastic human pituitaries

Am. J. Pathol.

(1997)

S.S. Millard et al.

A U-rich element in the 5′ untranslated region is necessary for the translation of p27 mRNA

Mol. Cell Biol.

(2000)

M. Ciaparrone et al.

Localization and expression of p27KIP1 in multistage colorectal carcinogenesis

Cancer Res.

(1998)

S.P. Singh et al.

Loss or altered subcellular localization of p27 in Barrett's associated adenocarcinoma

Cancer Res.

(1998)

V. Masciullo et al.

Frequent loss of expression of the cyclin-dependent kinase inhibitor p27 in epithelial ovarian cancer

Cancer Res.

(1999)

A. Sgambato et al.

Reduced expression and altered subcellular localization of the cyclin-dependent kinase inhibitor p27(Kip1) in human colon cancer

Mol. Carcinog.

(1999)

G. Orend et al.

Cytoplasmic displacement of cyclin E-cdk2 inhibitors p21Cip1 and p27Kip1 in anchorage-independent cells

Oncogene

(1998)

R. Piva et al.

Proteasome-dependent degradation of p27/kip1 in gliomas

J Neuropathol. Exp. Neurol.

(1999)

V. Esposito et al.

Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer

Cancer Res.

(1997)

M.L. Fero et al.

The murine gene p27Kip1 is haplo-insufficient for tumour suppression

Nature

(1998)

Cited by (265)

Updates on the genetics of multiple endocrine neoplasia
2024, Annales d'Endocrinologie
Multiple endocrine neoplasia (MEN) is a group of syndromes with a genetic predisposition to the appearance of endocrine tumors, and shows autosomal dominant transmission. The advent of molecular genetics has led to improvements in the management of MEN in terms of diagnosis, prognosis and therapy. The genetics of MEN is the subject of regular updates, which will be presented throughout this paper. MEN1, the first to be described, is associated with the MEN1 gene. MEN1 is well known in terms of the observed phenotype, with genetic analysis being conclusive in 90% of patients with a typical phenotype, but is negative in around 10% of families with MEN1. Improvement in analysis techniques and the identification of other genes responsable for phenocopies allows the resolution of some, but not all, cases, notably non-familial forms suspected to be fortuitous assocations with tumors. MEN4 is a rare phenocopy of MEN1 linked to constitutional mutations in the CDKN1B gene. Though it closely resembles the phenotype of MEN1, published data suggests the appearance of tumors is later and less frequent in MEN4. MEN2, which results from mutations in the RET oncogene, shows a strong genotype-phenotype correlation. This correlation is particularly evident in the major manifestation of MEN2, medullary thyroid carcinoma (MTC), in which disease aggressiveness is dependent on the pathogenic variant of RET. However, recent studies cast doubt on this correlation between MTC and pathogenic variant. Lastly, the recent description of families carrying a mutation in MAX, which is known to predispose to the development of pheochromocytoma and paraganglioma, and presents a phenotypic spectrum that evokes MEN, suggests the existence of another syndrome, MEN5.
Pathophysiology and genetics in pituitary tumors
2021, Pituitary Tumors: A Comprehensive and Interdisciplinary Approach
Pituitary tumors are monoclonal neoplasms whose pathogenesis is complex and still partly obscure. Germline mutations exist in around 5% of patients with pituitary tumors in isolated or syndromic settings. With the exception of AIP, which is mutated in 20% of young (< 18 years old) patients with pituitary macroadenomas, genes associated with genetic syndromes such as PRKAR1A, MEN1, GPR101, SDHx, and CDKN1B are rarely mutated in sporadic pituitary tumors. Oncogenes like HRAS and BRAF are rarely mutated in sporadic pituitary tumors, while TP53 mutations are limited to aggressive cases. Recurrent somatic mutational hotspots in GNAS, USP8, and in lesser extent USP48 are present in almost half of somatotroph and corticotroph tumors, respectively. Large-scale omics studies confirmed that with the exception of GNAS and USP8, there are no clear driver mutations for the majority of pituitary tumors, indicating the presence of unsuspecting genetic defects.
CDKN1B (p27) defects leading to pituitary tumors
2021, Gigantism and Acromegaly
In recent years, new insight into the etiopathogenesis of hereditary pituitary tumors has emerged. Several novel susceptibility genes for these tumors have been identified and among them is CDKN1B encoding the cell cycle regulator p27. Heterozygous germline mutations in CDKN1B are associated with the predisposition to multiple neuroendocrine tumors (NETs), including pituitary tumors. Patients carrying these mutations are affected by the Multiple Endocrine Neoplasia type 4 (MEN4) syndrome. In this chapter, we discuss the current state of knowledge of the function of p27; present clinical and basic findings related to the pituitary phenotype of MEN4 patients as well as the functional characterization of the CDKN1B mutations identified in these patients.
Prenatally androgenized female rats develop uterine hyperplasia when adult
2020, Molecular and Cellular Endocrinology
Prenatal hyperandrogenization (PH) is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal exposure to androgen excess on the uterus when animals reach their adulthood. We found that PH altered the morphology of the uteri that show a hyperplastic morphology with increased total uterine thickness as well as luminal epithelium thickness, with both enhanced and altered distribution of glands as compared with controls. Morphological alterations were associated with an unbalanced homeostasis as assessed by the expression of regulators of cell cycle progression and cell death dynamics. PH also causes disturbances in the cell cycle of the uterine tissue and dysregulates cell death and survival pathways leading to the development of uterine hyperplasia. These findings suggest that PH may have a deleterious effect on the uterus.
Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: A double-edged sword protein
2018, DNA Repair
The cell cycle is controlled by precise mechanisms to prevent malignancies such as cancer, and the cell needs these tight and advanced controls. Cyclin dependent kinase inhibitor p27 (also known as KIP₁) is a factor that inhibits the progression of the cell cycle by using specific molecular mechanisms. The inhibitory effect of p27 on the cell cycle is mediated by CDKs inhibition. Other important functions of p27 include cell proliferation, cell differentiation and apoptosis. Post- translational modification of p27 by phosphorylation and ubiquitination respectively regulates interaction between p27 and cyclin/CDK complex and degradation of p27. In this review, we focus on the multiple function of p27 in cell cycle regulation, apoptosis, epigenetic modifications and post- translational modification, and briefly discuss the mechanisms and factors that have important roles in p27 functions.
Diagnostic Pathology: Endocrine
2018, Diagnostic Pathology: Endocrine

View all citing articles on Scopus

¹: To whom correspondence and reprint requests should be addressed. Fax: (206) 667-5815. E-mail: [email protected].

View full text

Regular Articlep27Kip1: Regulation and Function of a Haploinsufficient Tumor Suppressor and Its Misregulation in Cancer

Abstract

Cell

Blood

Blood

Am. J. Pathol.

Am. J. Pathol.

Blood

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Gene

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

Cell

Trends Biochem. Sci.

J Biol. Chem.

A cell cycle-regulated inhibitor of cyclin-dependent kinases

Proc. Natl. Acad. Sci. USA

Inhibitors of mammalian G1 cyclin-dependent kinases

Genes Dev.

CDK inhibitors: Positive and negative regulators of G1-phase progression

Genes Dev.

Regulation of the cdk inhibitor p27 and its deregulation in cancer

J. Cell Physiol.

Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex [see comments]

Nature

Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27Kip1, to regions involved in human cancer

Cancer Res.

Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias

Cancer Res.

p27Kip1: Chromosomal mapping to 12p12–12p13.1 and absence of mutations in human tumors

Cancer Res.

The murine Cdkn2a gene (p27/Kip1) maps to distal chromosome 6 and is excluded as Pas1

Mamm. Genome

Allelotype analysis of childhood acute lymphoblastic leukemia

Cancer Res.

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

Br. J. Cancer

Deletion mapping at 12p12–13 in metastatic prostate cancer

Genes Chromosomes Cancer

Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies

Cancer Res.

p27 mutation found in breast cancer

Cancer Res.

Mutational analysis of the human cyclin-dependent kinase inhibitor p27kip1 in primary breast carcinomas

Hum. Genet.

The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer

Annu. Rev. Med.

Cancer epigenetics comes of age

Nature Genet.

The p27/Kip1 locus shows no loss of heterozygosity in human pituitary adenomas

J. Neurooncol.

Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer [see comments]

Nature Med.

Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas

Nature Med.

Transforming growth factor-beta, transforming growth factor-beta receptor II, and p27Kip1 expression in nontumorous and neoplastic human pituitaries

Am. J. Pathol.

A U-rich element in the 5′ untranslated region is necessary for the translation of p27 mRNA

Mol. Cell Biol.

Localization and expression of p27KIP1 in multistage colorectal carcinogenesis

Cancer Res.

Loss or altered subcellular localization of p27 in Barrett's associated adenocarcinoma

Cancer Res.

Frequent loss of expression of the cyclin-dependent kinase inhibitor p27 in epithelial ovarian cancer

Cancer Res.

Reduced expression and altered subcellular localization of the cyclin-dependent kinase inhibitor p27(Kip1) in human colon cancer

Mol. Carcinog.

Cytoplasmic displacement of cyclin E-cdk2 inhibitors p21Cip1 and p27Kip1 in anchorage-independent cells

Oncogene

Proteasome-dependent degradation of p27/kip1 in gliomas

J Neuropathol. Exp. Neurol.

Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer

Cancer Res.

Regular Article
p27^Kip1: Regulation and Function of a Haploinsufficient Tumor Suppressor and Its Misregulation in Cancer