Involvement of CUL4 Ubiquitin E3 Ligases in Regulating CDK Inhibitors Dacapo/p27Kip1 and Cyclin E Degradation

Higa, Leigh Ann; Yang, Xiaoming; Zheng, Jian‐Yu; Banks, Damon; Wu, Min; Ghosh, Pradip; Sun, Hong; Zhang, Hui

doi:10.4161/cc.5.1.2266

Cited by 107 publications

(141 citation statements)

References 45 publications

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“…In human cells, inactivation of Cul4A, another cullin protein, induces p27 stabilization and G1 cell cycle arrest (30,31). It has been speculated that the F-box protein Skp2 cooperates with Cul1-Skp1 as well as Cul4A-DDB1 to induce proteolysis of p27 (32).…”

Section: Discussionmentioning

confidence: 99%

Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression

Li¹

2010

Int J Oncol

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Abstract. Cullin1 (Cul1) serves as a rigid scaffold in SCF (Skp1/Cullin/Rbx1/F-box protein) complex, the largest family of ubiquitin-protein E3 ligases, and aberrant expression of Cul1 is involved in dysfunction of SCF E3 ligases. Previously, we found that Cul1 expression is increased in early stages of melanoma. In the present study, we further investigated the role of Cul1 in melanoma development. Our results showed that knockdown of Cul1 inhibits melanoma cell growth while overexpression of Cul1 enhances cell proliferation through the control of cell cycle progression. We also found that Cul1 regulates melanoma cell growth and cell cycle progression through degradation of p27 by functional SCF Skp2 complex. This study elucidates the role of Cul1 in melanoma cell proliferation and improves our understanding of increased expression of Cul1 in early stages of melanoma. IntroductionThe cutaneous malignant melanoma derived from epidermal melanocytes is the most serious type of skin cancer. The incidence of melanoma increases steadily in the order of 3-7% per year for fair-skinned Caucasian populations (1). In 1935, the lifetime risk for an American developing invasive melanoma was 1 in 1500. In 2007, this risk is 1 in 63 for invasive melanomas and 1 in 33 if in situ melanomas were included (2-4). With surgical excision, the early diagnosed melanomas are curable, however, up to 20% of patients will develop metastatic tumors due to its high capability of invasion and rapid metastasis to other organs (5,6). The prognosis for patients with advanced melanoma remains poor, and the 5-year survival rate for patients with distant metastases is less than 10% (7).Cancer development is the process by which normal cells are transformed into cancerous cells, which results from aberrant cellular responses to stimuli. This process is regulated by transcription, translation, post-translational modifications and degradation of key regulatory proteins which has a crucial role in maintaining and regulating cellular homeostasis (8,9). The ubiquitin-proteasome system controls the abundance of a number of cellular proteins, including p53, ß-catenin, p21, p27 and cyclins (10-12). Polyubiquitin conjugation of lysine residues in proteins as a result of collaboration with a ubiquitin-activating enzyme (E1), a ubiquitin-conjugation enzyme (E2), and a ubiquitin ligase (E3) is required for selective recognition and degradation by the 26S proteasome (13). Dysfunction of E3 ubiquitin ligases contributes to abnormal cell growth and differentiation (12). The SCF (Skp1/Cullin/Rbx1/F-box protein) complexes are the largest family of Cullin RING ligases (CRL) and ubiquitinate a broad range of proteins (14,15). As a rigid scaffold in SCF complex, Cullin1 (Cul1) plays a key role in SCF complex assembly and aberrant expression of Cul1 results in dysfunction of SCF E3 ligases. Loss of Cul1 results in early embryonic lethality and deregulation of cyclin E (16). Cul1 is modified through the covalent attachment of the ubiquitin-like small molecule Nedd8 and ...

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Section: Discussionmentioning

confidence: 99%

Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression

Li¹

2010

Int J Oncol

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“…The finding that CUL-4 orthologs in Drosophila and humans also negatively regulate the stability of CDK inhibitors of the CIP/KIP family provides the possibility that the latter pathway is also conserved. [49][50][51][52] What is the Role of CDKs in Regulating DNA Replication in Metazoa?…”

Section: Elegans Cul-4 Independently Regulates Both Cdc-6 and Cdt-mentioning

confidence: 99%

Control of the Cdc6 replication licensing factor in metazoa: The role of nuclear export and the CUL4 ubiquitin ligase

Kim¹,

Kipreos²

2008

Cell Cycle

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“…Although OVX also induced Cul4a which promotes G 1 cell cycle progression (Higa et al 2006), it suppressed AKT1 substrate 1 (Akt1S1), a proline-rich AKT substrate (Kovacina et al 2003). The AKT is known to inhibit apoptosis and stimulate cellular growth.…”

Section: Effects Of Ovxmentioning

confidence: 99%

Gender difference of androgen actions on skeletal muscle transcriptome

Yoshioka¹,

Boivin²,

Bolduc³

et al. 2007

Journal of Molecular Endocrinology

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Sarcopenia is related to metabolic syndrome in postmenopausal women. Hormone replacement therapies with androgens improve muscle functions by molecular mechanisms that are still unknown, at least partly because the skeletal muscle transcriptome has been less characterized in females. We performed the serial analysis of gene expression method in six experimental groups, intact (male and female), ovariectomy (OVX), OVXCdihydrotestosterone (DHT) injection 1, 3, or 24 h before kill in mice. The 438 transcript species differentially expressed between gender showed that females had higher expression levels of mRNA related to cytoskeleton/contractile apparatus and mitochondrial processes as well as protein, lipid, and amino acid metabolisms. In females, OVX and DHT modulated 109 and 128 transcript species respectively. OVX repressed transcripts of fast/glycolytic fiber, glycolysis, and glucose transport, whereas all these effects were reversed 3 h after the DHT injection. Moreover, DHT treatment induced transcripts which reduce intracellular Ca 2C level at early time points. These results may suggest that DHT treatment in OVX mice increases muscle contractility by affecting fiber distribution and intracellular Ca 2C concentration as well as improving glucose metabolism. On the other hand, transcripts of fast/oxidative fiber, oxidative phosphorylation, and ATP production were repressed 24 h after DHT administration. In our previous study using male mice, transcripts in oxidative phosphorylation and ATP production were induced 24 h after DHT injection (Yoshioka M, Boivin A, Ye P, Labrie F & St-Amand J 2006 Effects of dihydrotestosterone on skeletal muscle transcriptome in mice measured by serial analysis of gene expression. Journal of Molecular Endocrinology 36 247-259). These results demonstrate gender differences in DHT actions on skeletal muscle, and contribute to a precise understanding of the molecular mechanisms of androgen actions in the female skeletal muscle.

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Involvement of CUL4 Ubiquitin E3 Ligases in Regulating CDK Inhibitors Dacapo/p27Kip1 and Cyclin E Degradation

Cited by 107 publications

References 45 publications

Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression

Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression

Control of the Cdc6 replication licensing factor in metazoa: The role of nuclear export and the CUL4 ubiquitin ligase

Gender difference of androgen actions on skeletal muscle transcriptome

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