Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the cyclin-dependent kinase inhibitor p27(Kip1) (p27) is frequently reduced in human colorectal cancer, and this correlates with poor patient prognosis. To clarify the role of p27 in gastrointestinal (GI) cancer, we measured p27 expression, as well as the effect of germline deletion of p27, in 3 different mouse models of GI neoplasia. p27 expression was frequently reduced in GI tumors arising in 1,2-dimethylhydrazine (DMH) treated mice, and in Apc mutant Min/+ mice, but not in GI tumors arising in Smad3 mutant mice. Germline deletion of p27 resulted in accelerated tumor development and increased tumor cell proliferation in both DMH treated and Min/+ mice, but not in Smad3 mutant mice. p27 deficiency also led to increased adenoma to adenocarcinoma progression. These results indicate that reduction of p27 cooperates with mutations in Apc but not in Smad3 during GI tumorigenesis. Thus, tumor suppression by p27 is contingent on the specific oncogenic pathway that drives tumor development.
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PMID:Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice. 1208 50

The cyclin-dependent kinase (CDK) inhibitors p21(Cip1) and p27(Kip1) are induced in response to anti-proliferative stimuli and block G(1)/S-phase progression through the inhibition of CDK2. Although the cyclin E-CDK2 pathway is often deregulated in tumors the relative contribution of p21(Cip1) and p27(Kip1) to tumorigenesis is still unclear. The MYC transcription factor is an important regulator of the G(1)/S transition and its expression is frequently altered in tumors. Previous reports suggested that p27(Kip1) is a crucial G(1) target of MYC. Our study shows that in mice, deficiency for p27(Kip1) but not p21(Cip1) results in decreased survival to retrovirally-induced lymphomagenesis. Importantly, in such p27(Kip1) deficient lymphomas an increased frequency of Myc activation is observed. p27(Kip1) deficiency was also shown to collaborate with MYC overexpression in transgenic lymphoma models. Thus, in vivo, the capacity of MYC to promote tumor growth is fully retained and even enhanced upon p27(Kip1) loss. We show that in lymphocytes, MYC overexpression and p27(Kip1) deficiency independently stimulate CDK2 activity and augment the fraction of cells in S phase, in support of their distinct roles in tumorigenesis.
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PMID:Loss of p27(Kip1) but not p21(Cip1) decreases survival and synergizes with MYC in murine lymphomagenesis. 1211 May 86

We developed the AJBL6 transforming growth factor-beta 1 (TGF-beta1) heterozygous (HT) mouse by mating A/J mice with C57BL/6 TGF-beta1 HT mice that shows increased carcinogen-induced lung lesions with decreased latency to examine progressive events in lung tumorigenesis. Mouse cDNA macroarrays were used to identify cell cycle genes that are differentially regulated in ethyl carbamate-induced lung adenocarcinomas compared with normal lung tissue in AJBL6 TGF-beta1 HT mice using probes that were generated from tissues isolated using laser capture microdissection. While expression of the genes for cyclin D1, CDK4, and E2F1 increased in lung adenocarcinomas relative to normal lung, expression of p15(Ink4b), p16(Ink4a), p21(Cip1), p27(Kip1), p57(Kip2), and pRb genes decreased in comparison. Competitive RT-PCR showed that the levels of cyclin D1 and CDK4 mRNAs were 2- and 3-fold higher, respectively, in lung adenocarcinomas than in normal lung, while the mRNAs for p15(Ink4b), p16(Ink4a), p21(Cip1), p27(Kip1), and pRb were 3- to 4-fold lower in adenocarcinomas than in normal lung, thus validating the macroarray findings. Competitive RT-PCR of microdissected lesions also showed that the levels of cyclin D1 and CDK4 mRNAs increased significantly, while the mRNAs for p15(Ink4b) and p27(Kip1) decreased significantly as lung tumorigenesis progressed. Immunohistochemical staining for cyclin D1 and CDK4 showed staining in >80% of nuclei in adenocarcinomas compared with fewer than 20% of nuclei staining positively in normal lung. In contrast, while >60% of normal lung cells showed immunostaining for p15(Ink4b), p16(Ink4a), p21(Cip1), p27(Kip1), and pRb, staining for these proteins decreased in hyperplasias, adenomas, and adenocarcinomas. These data show that multiple components of the cyclin D1/CDK4/p16(Ink4a)/pRb signaling pathway are frequently altered early in lung lesions of AJBL6 TGF-beta1 HT mice that are induced by ethyl carbamate as a function of progressive lung carcinogenesis, suggesting that components of this pathway may be potential targets for gene therapy.
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PMID:Altered expression of G1/S regulatory genes occurs early and frequently in lung carcinogenesis in transforming growth factor-beta1 heterozygous mice. 1211 81

Apoptosis, or programmed cell death, is involved in many biological events, including tumorigenesis. Recently, it has been reported that two members of the Cip/Kip family of CDK inhibitors, p21(Cip1) and p27(Kip1), are involved in the regulation of apoptosis. Here, we report that selective expression of the third member in this family, p57(Kip2), potentiated staurosporine-induced apoptosis in HeLa cells. This pro-apoptotic effect was associated with an increased caspase-3 activity. In contrast, glucocorticoid treatment, despite inducing p57(Kip2) expression in HeLa cells, was found to have an inhibitory effect on staurosporine-induced apoptosis. This anti-apoptotic effect of glucocorticoids could be explained by a concomitant increase in Bcl-x(L) expression. The results presented in this study show that p57(Kip2) has a stimulatory effect on apoptosis induced by staurosporine, suggesting a role for p57(Kip2) in the response of tumor cells to cytotoxic drugs.
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PMID:A pro-apoptotic effect of the CDK inhibitor p57(Kip2) on staurosporine-induced apoptosis in HeLa cells. 1217 39

Multi-cellular spheroids (MCS) generated from tumor cells serve as excellent in vitro models for understanding the mechanisms of tumor progression and micro-metastasis. We have compared the expression of molecular markers with reference to their growth as conventional adherent monolayers (2-D) and anchorage independent cultures (3-D) using two mouse melanoma cell lines, B16F10 and Clone M3. The two cell lines differed in their ability to form spheroids with respect to their aggregation potential, with B16F10 forming large clusters compared to Clone M3. A panel of molecular markers comprising cell adhesion molecules, cyclin dependent kinase inhibitors and members of the cadherin-catenin complex were analyzed by flow cytometry in 2-D and 3-D cultures. There was a distinct difference in the patterns of expression of CD44(S) and variant isoforms v3, v10 in spheroids compared to cells grown as monolayers in both cell lines. Also, there was an increase in cells positive for CDK inhibitor p27 in 3-D cultures from the B16F10 cell line. The expression of alpha and gamma catenin was down regulated in spheroids. As these molecules are implicated in the regulation of cell proliferation, alterations in the expression of these molecules in 3-D cultures compared to their 2-D counterparts suggests the importance of spheroids as experimental model for tumorigenesis.
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PMID:Differential expression of CD44(S) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines. 1219 73

In thyroid tumors, several cell cycle regulators have been found to be altered or overexpressed, but no data exist on E2F transcription factors. Such factors (E2F-1 in particular) act as the final effectors in the retinoblastoma pathway but are also involved in apoptosis. To analyze E2F-1 expression in thyroid neoplasms, we investigated 73 thyroid tumors, including 28 oxyphilic and 45 nonoxyphilic lesions, by immunohistochemistry, in parallel with other cell cycle-related proteins (p27, pRb, p53, and Ki67). p27, Ki-67, pRb, and p53 expression patterns generally overlapped the literature data. E2F-1 was expressed in all thyroid tumor types, both benign and malignant, with no statistical correlation with proliferative status (except for anaplastic carcinoma). A significantly higher percentage of tumor cells expressed E2F-1 in oxyphilic adenomas (71.5%) and oxyphilic carcinomas (66.1%) as compared with that of the corresponding nonoxyphilic lesions (30.8% and 34.5%, respectively; P < .05). These same tumors had a relatively low proliferative index. Therefore, because oxyphilic tumors of the thyroid show peculiar morphological, phenotypic, and ultrastructural features, possibly related to their particular metabolic conditions, it is possible that E2F-1 overexpression is linked to activities other than cell cycle entry in oxyphilic tumors. In conclusion, E2F-1 is expressed in both benign and malignant thyroid tumors, thus suggesting a wide involvement of the retinoblastoma pathway in thyroid tumorigenesis. In addition, in oxyphilic tumors, more than two thirds of tumor cells express E2F-1, an event possibly linked to proapoptotic rather than proliferative signals in such neoplasms.
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PMID:E2F-1 transcription factor is overexpressed in oxyphilic thyroid tumors. 1237 49

Transforming growth factor beta (TGF-beta) induces cell cycle arrest of most nontransformed epithelial cell lines. In contrast, many human carcinomas are refractory to the growth-inhibitory effect of TGF-beta. TGF-beta overexpression inhibits tumorigenesis, and abolition of TGF-beta signaling accelerates tumorigenesis, suggesting that TGF-beta acts as a tumor suppressor in mouse models of cancer. A screen to identify agents that potentiate TGF-beta-induced growth arrest demonstrated that the potential anticancer agent rapamycin cooperated with TGF-beta to induce growth arrest in multiple cell lines. Rapamycin also augmented the ability of TGF-beta to inhibit the proliferation of E2F1-, c-Myc-, and (V12)H-Ras-transformed cells, even though these cells were insensitive to TGF-beta-mediated growth arrest in the absence of rapamycin. Rapamycin potentiation of TGF-beta-induced growth arrest could not be explained by increases in TGF-beta receptor levels or rapamycin-induced dissociation of FKBP12 from the TGF-beta type I receptor. Significantly, TGF-beta and rapamycin cooperated to induce growth inhibition of human carcinoma cells that are resistant to TGF-beta-induced growth arrest, and arrest correlated with a suppression of Cdk2 kinase activity. Inhibition of Cdk2 activity was associated with increased binding of p21 and p27 to Cdk2 and decreased phosphorylation of Cdk2 on Thr(160). Increased p21 and p27 binding to Cdk2 was accompanied by decreased p130, p107, and E2F4 binding to Cdk2. Together, these results indicate that rapamycin and TGF-beta cooperate to inhibit the proliferation of nontransformed cells and cancer cells by acting in concert to inhibit Cdk2 activity.
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PMID:Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. 1241 22

The F-box protein Skp2 (Fbl1) is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. Its overexpression has been implicated in cell transformation and oncogenesis in both in vitro and in vivo models. In this study, we investigated its role in human prostate cancer progression. Immunohistochemical analysis was performed on formalin-fixed paraffin sections of 622 radical prostatectomy specimens, 74 prostatic intraepithelial neoplasm specimens, as well as in 4 normal prostate organ donors assembled into tissue microarrays. We found that both luminal and basal epithelial cells in normal prostate had very low Skp2 levels, but Skp2 levels and labeling frequency increased dramatically in both premalignant lesions of prostatic intraepithelial neoplasm (P = 0.0252) and in prostate cancer (P = 0.0037). The Skp2 labeling frequency in cancer was positively correlated with preoperative serum prostate-specific antigen level (P = 0.0499) and Gleason score (P = 0.0002), whereas the Skp2 index was positively correlated with extraprostatic extension (P = 0.0454), clinical stage (P = 0.0170), as well as Gleason score (P = 0.0002). Kaplan-Meier analysis revealed that a higher Skp2 labeling index (>10) was a significant predictor of shorter biochemical recurrence-free survival time after radical prostatectomy (P < 0.0363, log-rank test). An inverse correlation of Skp2 was observed with both its biochemical target p27 expression in prostate cancer (P = 0.0003) and with its putative negative regulator, the PTEN tumor suppressor protein (P = 0.0444). These data suggest that induction of Skp2 may be causally linked with decreased levels of p27 in prostate cancer and implicate PTEN in the regulation of Skp2 expression in vivo, as previous tissue culture experiments have suggested.
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PMID:Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. 1242 29

Events that contribute to tumor formation include mutations in the ras gene and loss or inactivation of cell cycle inhibitors such as p21(Cip1) and p27(Kip1). In our previous publication, we showed that mice expressing the MMTV/v-Ha-ras transgene developed tumors earlier and at higher multiplicities in the absence than in the presence of p21(Cip1). To further evaluate the combinatorial role of genetic alterations and loss of cell cycle inhibitors in tumorigenesis, we performed two companion studies. In the first study, wild type and p21(Cip1)-null mice were exposed to the chemical carcinogen, urethane. Similar to its effects in v-Ha-ras mice, loss of p21(Cip1) accelerated tumor onset and increased tumor multiplicity in urethane-treated mice. Lung tumors were the predominant tumor type in urethane-treated mice regardless of p21(Cip1) status. In the second study, tumor formation was monitored in v-Ha-ras mice expressing or lacking p27(Kip1). Unlike p21(Cip1), the absence of p27(Kip1) had no effect on the timing or multiplicity of tumor formation, which was largely restricted to mammary and salivary glands. However, once tumors appeared, they grew faster in p27(Kip1)-null mice than in p27(Kip1)-wild type mice. Increases in growth rate were particularly striking for salivary tumors in ras/p27(-/-) mice. Loss of p21(Cip1), on the other hand, had no effect on tumor growth rate in v-Ha-ras mice. Collectively, our data suggest that p21(Cip1) suppresses tumor formation elicited by multiple agents and that p21(Cip1) and p27(Kip1) suppress tumor formation in different ways.
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PMID:Loss of the cell cycle inhibitors p21(Cip1) and p27(Kip1) enhances tumorigenesis in knockout mouse models. 1246 68

p27 acts as a critical negative regulator of the cell cycle by inhibiting the activity of cyclin/cdk complexes during G0 and G1. Degradation of p27 is a critical event for the G1/S transition and occurs through ubiquitination by SCF(Skp2) and subsequent degradation by the 26S-proteasome. A tumor suppressing function of p27 has been demonstrated in mouse models and studies of human tumors. More recent evidence suggests that Skp2, the specific recognition factor for p27 ubiquitination, has oncogenic properties. This review will focus on the regulation of p27 proteolysis and its consequences for tumorigenesis.
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PMID:Deregulated degradation of the cdk inhibitor p27 and malignant transformation. 1250 55


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