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Cullin family proteins and tumorigenesis: genetic association and molecular mechanisms.

Chen Z, Sui J, Zhang F, Zhang C - J Cancer (2015)

Bottom Line: Cullin family proteins function as scaffolds to form numerous E3 ubiquitin ligases with RING proteins, adaptor proteins and substrate recognition receptors.These E3 ligases further recognize numerous substrates to participate in a variety of cellular processes, such as DNA damage and repair, cell death and cell cycle progression.Clinically, cullin-associated E3 ligases have been identified to involve numerous human diseases, especially with regard to multiple cancer types.

View Article: PubMed Central - PubMed

Affiliation: 1. Orthopedics Department, Changhai Hospital Affiliated to Second Military Medical University, Shanghai, China, 200433.

ABSTRACT
Cullin family proteins function as scaffolds to form numerous E3 ubiquitin ligases with RING proteins, adaptor proteins and substrate recognition receptors. These E3 ligases further recognize numerous substrates to participate in a variety of cellular processes, such as DNA damage and repair, cell death and cell cycle progression. Clinically, cullin-associated E3 ligases have been identified to involve numerous human diseases, especially with regard to multiple cancer types. Over the past few years, our understanding of cullin proteins and their functions in genome stability and tumorigenesis has expanded enormously. Herein, this review briefly provides current perspectives on cullin protein functions, and mainly summarizes and discusses molecular mechanisms of cullin proteins in tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

Models of cullin-RING E3 ligases. Cullin proteins recruit adaptor proteins (Skp1 for CUL1 and CUL7, Elongin B/C for CUL2 and CUL5, BTB protein for CUL3, and DDB1 for CUL4A and 4B), receptor proteins (F-box proteins for CUL1, VHL-box for CUL2, DCAFs for CUL4A and 4B, SOCS for CUL5, and FBXW8 for CUL7), and RING protein (RBX1/2) to form CRL E3 ligases that promote ubiquitin to transfer from RBX1/RBX2-bound E2 to a substrates 5. (A) CRL1; (B) CRL2; (C) CRL3; (D) CRL4; (E) CRL5; (F) CRL7; (G) CRL9.
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Figure 2: Models of cullin-RING E3 ligases. Cullin proteins recruit adaptor proteins (Skp1 for CUL1 and CUL7, Elongin B/C for CUL2 and CUL5, BTB protein for CUL3, and DDB1 for CUL4A and 4B), receptor proteins (F-box proteins for CUL1, VHL-box for CUL2, DCAFs for CUL4A and 4B, SOCS for CUL5, and FBXW8 for CUL7), and RING protein (RBX1/2) to form CRL E3 ligases that promote ubiquitin to transfer from RBX1/RBX2-bound E2 to a substrates 5. (A) CRL1; (B) CRL2; (C) CRL3; (D) CRL4; (E) CRL5; (F) CRL7; (G) CRL9.

Mentions: Generally, CRLs consist of four components: cullins, RINGs, adaptor proteins and substrate recognition receptors 5. The two RING-box components (RBX1 and RBX2) can bind to two zinc atoms via a C3H2C3 motif to form the RING finger domain, which is required for the activity of CRLs 6. Except for CUL9, all of the other cullin proteins in human can interact with RBX1 or RBX2 through an evolutionarily conserved CH domain at the C-terminus 5. Moreover, the human genome contains four adaptor proteins, including S-phase kinase-associated protein 1 (Skp1), Elongin B and C, and damaged DNA binding protein 1 (DDB1) 7. Of them, Skp1 generally interacts with CUL1 and CUL7; Elongin B and C interact with CUL2 and CUL5; and DDB1 interacts with CUL4A and CUL4B (Figure 2) 7. In addition, BTB (Broad complex, Tramtrack, Bric-a-brac) proteins have been reported to function as adaptors interacting with CUL3 8. However, it has not been found adaptor protein that interacts with CUL9 to date (Figure 2). These CRLs have been identified to harbor more than 400 substrate recognition receptors in human genome, including 78 F-box proteins for CRL1, 80 SOCS (suppressor of cytokine signaling) proteins for CRL2/5, ~200 BTB proteins for CRL3, and 90 DCAF (DDB1 and CUL4-associated factors) proteins for CRL4A/B 5, 9. These substrate recognition receptors further ubiquitinate and degrade thousands of substrates 5, controlling multiple cellular processes, such as cell cycle regulation, gene transcription, apoptosis, DNA damage and repair, chromatin remodeling, oxidative stress response, and signal transduction 5.


Cullin family proteins and tumorigenesis: genetic association and molecular mechanisms.

Chen Z, Sui J, Zhang F, Zhang C - J Cancer (2015)

Models of cullin-RING E3 ligases. Cullin proteins recruit adaptor proteins (Skp1 for CUL1 and CUL7, Elongin B/C for CUL2 and CUL5, BTB protein for CUL3, and DDB1 for CUL4A and 4B), receptor proteins (F-box proteins for CUL1, VHL-box for CUL2, DCAFs for CUL4A and 4B, SOCS for CUL5, and FBXW8 for CUL7), and RING protein (RBX1/2) to form CRL E3 ligases that promote ubiquitin to transfer from RBX1/RBX2-bound E2 to a substrates 5. (A) CRL1; (B) CRL2; (C) CRL3; (D) CRL4; (E) CRL5; (F) CRL7; (G) CRL9.
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Related In: Results  -  Collection

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Figure 2: Models of cullin-RING E3 ligases. Cullin proteins recruit adaptor proteins (Skp1 for CUL1 and CUL7, Elongin B/C for CUL2 and CUL5, BTB protein for CUL3, and DDB1 for CUL4A and 4B), receptor proteins (F-box proteins for CUL1, VHL-box for CUL2, DCAFs for CUL4A and 4B, SOCS for CUL5, and FBXW8 for CUL7), and RING protein (RBX1/2) to form CRL E3 ligases that promote ubiquitin to transfer from RBX1/RBX2-bound E2 to a substrates 5. (A) CRL1; (B) CRL2; (C) CRL3; (D) CRL4; (E) CRL5; (F) CRL7; (G) CRL9.
Mentions: Generally, CRLs consist of four components: cullins, RINGs, adaptor proteins and substrate recognition receptors 5. The two RING-box components (RBX1 and RBX2) can bind to two zinc atoms via a C3H2C3 motif to form the RING finger domain, which is required for the activity of CRLs 6. Except for CUL9, all of the other cullin proteins in human can interact with RBX1 or RBX2 through an evolutionarily conserved CH domain at the C-terminus 5. Moreover, the human genome contains four adaptor proteins, including S-phase kinase-associated protein 1 (Skp1), Elongin B and C, and damaged DNA binding protein 1 (DDB1) 7. Of them, Skp1 generally interacts with CUL1 and CUL7; Elongin B and C interact with CUL2 and CUL5; and DDB1 interacts with CUL4A and CUL4B (Figure 2) 7. In addition, BTB (Broad complex, Tramtrack, Bric-a-brac) proteins have been reported to function as adaptors interacting with CUL3 8. However, it has not been found adaptor protein that interacts with CUL9 to date (Figure 2). These CRLs have been identified to harbor more than 400 substrate recognition receptors in human genome, including 78 F-box proteins for CRL1, 80 SOCS (suppressor of cytokine signaling) proteins for CRL2/5, ~200 BTB proteins for CRL3, and 90 DCAF (DDB1 and CUL4-associated factors) proteins for CRL4A/B 5, 9. These substrate recognition receptors further ubiquitinate and degrade thousands of substrates 5, controlling multiple cellular processes, such as cell cycle regulation, gene transcription, apoptosis, DNA damage and repair, chromatin remodeling, oxidative stress response, and signal transduction 5.

Bottom Line: Cullin family proteins function as scaffolds to form numerous E3 ubiquitin ligases with RING proteins, adaptor proteins and substrate recognition receptors.These E3 ligases further recognize numerous substrates to participate in a variety of cellular processes, such as DNA damage and repair, cell death and cell cycle progression.Clinically, cullin-associated E3 ligases have been identified to involve numerous human diseases, especially with regard to multiple cancer types.

View Article: PubMed Central - PubMed

Affiliation: 1. Orthopedics Department, Changhai Hospital Affiliated to Second Military Medical University, Shanghai, China, 200433.

ABSTRACT
Cullin family proteins function as scaffolds to form numerous E3 ubiquitin ligases with RING proteins, adaptor proteins and substrate recognition receptors. These E3 ligases further recognize numerous substrates to participate in a variety of cellular processes, such as DNA damage and repair, cell death and cell cycle progression. Clinically, cullin-associated E3 ligases have been identified to involve numerous human diseases, especially with regard to multiple cancer types. Over the past few years, our understanding of cullin proteins and their functions in genome stability and tumorigenesis has expanded enormously. Herein, this review briefly provides current perspectives on cullin protein functions, and mainly summarizes and discusses molecular mechanisms of cullin proteins in tumorigenesis.

No MeSH data available.


Related in: MedlinePlus