Enhanced Growth of Mice Lacking the Cyclin-Dependent Kinase Inhibitor Function of p27

Kiyokawa, Hiroaki; Kineman, Rhonda D.; Manova‐Todorova, Katia; Soares, Vera; Hoffman, Eva A.; Ono, M.; Khanam, Dilruba; Hayday, Adrian; Frohman, Lawrence A.; Koff, Andrew

doi:10.1016/s0092-8674(00)81238-6

Cited by 1,168 publications

(980 citation statements)

References 39 publications

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“…In the absence of p27 (p277/7) growth rates were also accelerated and body weights achieved values similar to p27+/+, hGHRH mice. These observations are consistent with those reported for the original MThGHRH (Hammer et al, 1985;Mayo et al, 1988) and p277/7 (Nakayama et al, 1996;Kiyokawa et al, 1996;Fero et al, 1996) mouse strains, indicating that alterations in the genetic background did not signi®cantly alter the e ect of hGHRH transgene expression or p27-de®ciency on body growth. Reduction or elimination of p27 (+/7 or 7/7) accelerated the growth promoting e ects of the MT-hGHRH transgene in both male and female mice, with the most dramatic e ects observed in p277/7, hGHRH mice ( Figure 1).…”

Section: Body Weightsupporting

confidence: 90%

“…The p277/7 mice in this study displayed generalized organomegaly with disproportionate enlargement of the spleen, pituitary, testis and ovaries (Table 1A,B and Figure 2), as previously reported (Nakayama et al, 1996;Kiyokawa et al, 1996;Fero et al, 1996). In p27+/+, hGHRH mice, as in the original MT-hGHRH mouse strain (Hammer et al, 1985;Mayo et al, 1988), the pituitary, liver, spleen, heart and kidneys were increased in size, compared to their wildtype (p27+/+) littermates (Table 1A,B), with disproportionate enlargement of the pituitary and liver (Figure 2).…”

Section: Organ Weightssupporting

confidence: 89%

“…Mice with homozygous disruption of the p27 gene (p277/7) are 15 ± 30% larger than their heterozygous (p27+/7) and wildtype (p27+/+) littermates (Nakayama et al, 1996;Kiyokawa et al, 1996;Fero et al, 1996). The increase in body weight is due to generalized organomegaly in addition to disproportionate enlargement of the spleen, thymus, testis, ovary and pituitary.…”

Section: Introductionmentioning

confidence: 99%

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p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

et al. 2000

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p27 Kip1 (p27) controls cell cycle progression by binding to and inhibiting the activity of cyclin dependent kinases. Disruption of the p27 gene in mice (p277/7) results in increased body growth with a disproportionate enlargement of the spleen, thymus, testis, ovary and pituitary. The increase in pituitary size is due to selective hyperplasia of the intermediate lobe (IL) while the anterior lobe (AL) is not overtly a ected. p27 heterozygous mice (p27+/7), as well as p277/7 mice, are hypersensitive to radiation-and chemical-induced tumors compared to wildtype (p27+/+) littermates. Therefore, unlike classical tumor suppressors, only a reduction in p27 levels is necessary to predispose tissues to secondary tumor promoters. Consistent with these studies is the fact that the p27 gene sequence and mRNA levels appear normal in human pituitary adenomas while p27 protein levels are decreased. Therefore, a reduction in p27 levels could be su cient to sensitize pituitary cells to tumorigenic factors. To test this hypothesis, metallothionein promoter-driven, human growth hormone-releasing hormone (MT-hGHRH) transgenic mice, that exhibit somatotrope hyperplasia before 9 months of age and subsequent adenoma formation with 30 ± 40% penetrance, were crossbred with p27+/7 mice for two successive generations to produce p27+/+, p27+/7 and p277/7 mice that expressed the hGHRH transgene. At 10 ± 12 weeks of age, p277/7 and p27+/+, hGHRH mice were larger than their p27+/+ littermates and displayed characteristic hyperplasia of the IL and AL, respectively. Expression of the hGHRH transgene in both p27+/7 and p277/7 mice selectively expanded the population of somatotropes within the AL, where pituitaries of p27+/7, hGHRH and p277/7, hGHRH mice were two-and ®vefold larger than p27+/+, hGHRH pituitaries, respectively. There was also a synergistic e ect of hGHRH transgene expression and p27-de®ciency on liver, spleen and ovarian growth. At 6 ± 8 months of age, 83% of p27+/7, hGHRH mice displayed macroscopic AL adenomas (4100 mg), while all pituitaries from p27+/+, hGHRH mice remained hyperplastic (520 mg). In contrast to the dramatic e ects of p27-de®ciency on hGHRH-induced organ growth, elimination of p53, by crossbreeding MT-hGHRH mice to p53-de®cient mice, did not augment the hyperplastic/ tumorigenic e ects of hGHRH transgene expression.Taken together these results demonstrate that a reduction in p27 expression is su cient to sensitize somatotropes to the proliferative actions of excess GHRH, resulting in the earlier appearance and increased penetrance of hGHRH-induced pituitary tumors.

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Section: Body Weightsupporting

confidence: 90%

Section: Organ Weightssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

et al. 2000

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“…The importance of p27 Kip1 in the regulation of T-cell proliferation Nourse et al, 1994) has also been con®rmed by studies on p27 Kip1 -null mice (Fero et al, 1996;Kiyokawa et al, 1996;Nakayama et al, 1996). These animals were presented with increased proliferation of thymocytes, resulting in thymic hyperplasia and an increased responsiveness of splenic and thymic T-cells to IL-2, which, in turn, correlated with higher cyclin E-associated kinase activity.…”

Section: Discussionmentioning

confidence: 88%

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

et al. 1999

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“…First, it was reported that proteasome-mediated degradation of p27 protein occurred during the cell cycle and that this degradation was increased in a subset of tumors with poor prognosis (24,25). In addition, the generation of a murine model "null" for p27 revealed that knockout mice had a generalized hyperplasia and they were prone to the development of tumors (26,27). It was reported that normal prostate cells had abundant p27 protein and high levels of p27 messenger.…”

mentioning

confidence: 99%

Applications of Molecular Diagnostics: Solid Tumor Genetics Can Determine Clinical Treatment Protocols

Cordon‐Cardo

2001

Modern Pathology

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Solid tumor diagnosis is now entering an era in which molecular genetics plays an important role. Clinical trials have shown different responses to various therapies that correlate with molecular alterations. Biological determinants related to treatment response markers aimed at individualized therapies are being defined and implemented. Patients are now being treated based on the profile of molecular genetic alterations in individual tumors. Protocols based on molecular markers will increase the chances for cure by opting for the right management approach. They also will improve, in most situations, the quality of life of patients with cancer, for example by facilitating organ preservation strategies. The molecular characterization therefore has an important prognostic and practical role in diagnosis.

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Enhanced Growth of Mice Lacking the Cyclin-Dependent Kinase Inhibitor Function of p27

Cited by 1,168 publications

References 39 publications

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

Applications of Molecular Diagnostics: Solid Tumor Genetics Can Determine Clinical Treatment Protocols

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