Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Bloom, Joanna; Pagano, Michele

doi:10.1016/s1044-579x(02)00098-6

Cited by 338 publications

(330 citation statements)

References 61 publications

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“…1,2 The function of cdk is regulated by phosphorylation and dephosphorylation of the catalytic subunit, and by association with activating subunits called cyclins. The cdk inhibitors suppress the activity of the cyclin/cyclindependent kinase complexes.…”

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confidence: 99%

“…[1][2][3] Disruption of the cell cycle control is considered a hallmark of tumorigenesis and plays an important role in tumor progression. 1,4 There are two major families of cdk inhibitors, one being the Ink4 family and the other is Cip/Kip family. p27 Kip1 (p27) belongs to the Cip/Kip family and is a critical, universal cdk-inhibitory protein.…”

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confidence: 99%

“…1,5,6 When located in the nucleus, p27 is active and effectively inhibits cdk. Upon mitogenic stimuli, a fraction of p27 is translocated from the nucleus in the cytoplasm, reducing its nuclear concentration and the cells proliferate under unrestricted cdk activity.…”

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confidence: 99%

“…Although the mechanism underlying p27 deregulation in human cancer is poorly understood, several studies have shown that p27 is an independent prognostic marker in many human cancers. 1,7 It has been generally accepted that decreased p27 expression correlates with higher tumor grade and poor survival rates among patients with tumors of different histogenesis including, lung, colon, breast, and ovarian carcinomas. [8][9][10][11][12] Some tumors (eg, colon, esophagus, endometrial carcinomas) show increased p27 expression when compared with normal tissues, thus suggesting the existence of alternate mechanisms blocking the p27 inhibitory function over cellular proliferation.…”

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confidence: 99%

“…[13][14][15][16] There are several possible mechanisms involved in cancer-associated abnormalities of p27 expression. 1,17,18 It has been shown that, although p27 protein is downregulated in human tumors, p27 mRNA is not, eliminating the possibility of transcriptional mechanisms as the cause of this decrease. 1 Also, mutations of the gene encoding p27 are rare, suggesting that alterations in mechanisms regulating its degradation are more likely to be involved.…”

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confidence: 99%

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Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions

Ivan

Diwan²,

Esteva³

et al. 2004

Modern Pathology

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Decreased expression of p27 (a cyclin-dependent kinase inhibitor) is an adverse prognostic marker in a diverse array of human cancers. The purpose of this study was to investigate the expression of p27 and Jab1 (a protein involved in p27 degradation) in melanocytic lesions, and to identify their possible participation in melanoma progression. A tissue microarray was constructed using formalin-fixed, paraffin-embedded archival tissue blocks of 94 melanocytic lesions including 19 benign nevi, 21 dysplastic nevi, 23 melanomas, and 31 metastatic melanomas. The expression of p27 and Jab1 was evaluated by immunohistochemistry. The association between p27, Jab1, and clinicopathological parameters was analyzed using v 2 and Fisher's exact tests. Nonparametric Pearson's rank correlation was applied to evaluate the relationship between p27 and Jab1 expression. p27 was expressed in 15 (88%) nevi, 18 (95%) dysplastic nevi, 11 (50%) melanomas, and only in four (13%) of the metastatic melanomas (Po0.001). Jab1 was expressed in 14 (82%) standard nevi, 18 (95%) dysplastic nevi, 17 (77%) melanomas, and 16 (53%) of the metastatic melanomas (Po0.01). In metastatic melanomas, there was a negative correlation between p27 and Jab1 expression (r ¼ À0.166). The low levels of p27 in primary and metastatic melanoma cases may explain the high proliferation rate of such lesions. Also, the relative high expression of Jab1 in metastatic melanoma, associated with low levels of p27, suggests that Jab1 may be involved in survival and proliferation of metastatic melanoma cells.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions

Ivan

Diwan²,

Esteva³

et al. 2004

Modern Pathology

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Lysosome‐dependent FOXA1 ubiquitination contributes to luminal lineage of advanced prostate cancer

Celada,

Li,

Celada

et al. 2023

Molecular Oncology

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Changes in FOXA1 (forkhead box protein A1) protein levels are well associated with prostate cancer (PCa) progression. Unfortunately, direct targeting of FOXA1 in progressive PCa remains challenging due to variations in FOXA1 protein levels, increased FOXA1 mutations at different stages of PCa, and elusive post‐translational FOXA1 regulating mechanisms. Here, we show that SKP2 (S‐phase kinase‐associated protein 2) catalyzes K6‐ and K29‐linked polyubiquitination of FOXA1 for lysosomal‐dependent degradation. Our data indicate increased SKP2:FOXA1 protein ratios in stage IV human PCa compared to stages I‐III, together with a strong inverse correlation (r=‐0.9659) between SKP2 and FOXA1 levels, suggesting that SKP2‐FOXA1 protein interactions play a significant role in PCa progression. Prostate tumors of Pten/Trp53 mice displayed increased Skp2‐Foxa1‐Pcna signaling and colocalization, whereas disruption of the Skp2‐Foxa1 interplay in Pten/Trp53/Skp2 triple‐null mice demonstrated decreased Pcna levels and increased expression of Foxa1 and luminal positive cells. Treatment of xenograft mice with the SKP2 inhibitor SZL P1‐41 decreased tumor proliferation, SKP2:FOXA1 ratios and colocalization. Thus, our results highlight the significance of the SKP2‐FOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control.

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Ubiquitin-Proteasome System for Controlling Cellular Protein Levels

Glickman

Ciechanover

2006

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Cited by 338 publications

References 61 publications

Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions

Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions

Lysosome‐dependent FOXA1 ubiquitination contributes to luminal lineage of advanced prostate cancer

Ubiquitin-Proteasome System for Controlling Cellular Protein Levels

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