Mutation and expression analysis of the p27/kip1 gene in corticotrophin-secreting tumours

Dahia, Patricia L.M.; Aguiar, Ricardo C.T.; Honegger, Juergen; Fahlbush, R.; Jordan, Suzanne; Lowe, David; Lü, Xin; Clayton, Richard N.; Besser, G. M.; Grossman, A.

doi:10.1038/sj.onc.1201516

Cited by 117 publications

(72 citation statements)

References 25 publications

(46 reference statements)

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“…Although p27 protein levels clearly¯uctuate during progression through the cell cycle, p27 mRNA levels remain relatively constant (Hengst and Reed, 1996). Likewise, in the majority of human neoplasias, including pituitary adenomas, p27 mRNA levels do not di er from those observed in normal tissue, while p27 protein levels are reduced (Tanaka et al, 1997;Takeuchi et al, 1998;Dahia et al, 1998;Lloyd et al, 1997;Jin et al, 1997;Bamberger et al, 1999a;Lidhar et al, 1999;Tsihlias et al, 1999). Taken together these observations suggest that the primary regulation of p27 levels is post-transcriptional and that a defect in this process, which might include a decrease in p27 protein synthesis or an increase in p27 protein degradation, may contribute to neoplastic transformation.…”

Section: Discussionmentioning

confidence: 98%

“…p27 gene mutations are rarely found in human pituitary tumors (Ikeda et al, 1997;Tanaka et al, 1997;Takeuchi et al, 1998;Dahia et al, 1998) and p27 mRNA levels are reported to be normal in many pituitary tumor subtypes (Tanaka et al, 1997;Takeuchi et al, 1998;Dahia et al, 1998). However pituitary adenomas (LH/FSH, TSH, ACTH, GH/PRL and nonfunctioning) have lower levels of p27 protein compared to normal pituitary tissue Jin et al, 1997;Bamberger et al, 1999a;Lidhar et al, 1999).…”

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: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

et al. 2000

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“…Although p27 appears to function as a haploinsufficient tumor suppressor in mouse models, in human cancers loss of a single allele of the gene encoding p27 has been infrequently observed, and mutation of the second allele occurs only in very rare cases [41][42][43][44][45]. This evidence suggests that Cdkn1b gene deletion is an uncommon event in the development of human malignancies.…”

Section: P27 and Human Cancersmentioning

confidence: 99%

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Bloom

Pagano

2003

Seminars in Cancer Biology

338

317

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“…Previous studies have shown that p27 is consistently and frequently downregulated in corticotropinomas, but not in other types of pituitary adenomas (Dahia et al 1998). Moreover, a crucial role for p27 in the regulation of the proliferation of pituitary proopiomelanocortin (POMC) cells producing ACTH has also been demonstrated in animal studies, and p27-deficient mice develop POMC tumors at high frequencies (Fero et al 1996).…”

Section: Discussionmentioning

confidence: 97%

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

Sekiya

Bronstein

Benfini

et al. 2014

Endocrine-Related Cancer

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Germline mutations in p27 kip1 are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, nZ252; pheochromocytomas, nZ125; medullary thyroid carcinoma, nZ51; and parathyroid adenomas, nZ19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (PZ0.01), particularly for those with ACTH-secreting pituitary adenomas (PZ0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.

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Mutation and expression analysis of the p27/kip1 gene in corticotrophin-secreting tumours

Cited by 117 publications

References 25 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

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

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