Molecule Information

General Information of the Molecule (ID: Mol00311)

• Name: Cullin-4A (CUL4A) ,Homo sapiens
• Synonyms: CUL-4A
• Molecule Type: Protein
• Gene Name: CUL4A
• Gene ID: 8451
• Location: chr13:113208193-113267108[+]
• Sequence:
  MADEAPRKGSFSALVGRTNGLTKPAALAAAPAKPGGAGGSKKLVIKNFRDRPRLPDNYTQ
  DTWRKLHEAVRAVQSSTSIRYNLEELYQAVENLCSHKVSPMLYKQLRQACEDHVQAQILP
  FREDSLDSVLFLKKINTCWQDHCRQMIMIRSIFLFLDRTYVLQNSTLPSIWDMGLELFRT
  HIISDKMVQSKTIDGILLLIERERSGEAVDRSLLRSLLGMLSDLQVYKDSFELKFLEETN
  CLYAAEGQRLMQEREVPEYLNHVSKRLEEEGDRVITYLDHSTQKPLIACVEKQLLGEHLT
  AILQKGLDHLLDENRVPDLAQMYQLFSRVRGGQQALLQHWSEYIKTFGTAIVINPEKDKD
  MVQDLLDFKDKVDHVIEVCFQKNERFVNLMKESFETFINKRPNKPAELIAKHVDSKLRAG
  NKEATDEELERTLDKIMILFRFIHGKDVFEAFYKKDLAKRLLVGKSASVDAEKSMLSKLK
  HECGAAFTSKLEGMFKDMELSKDIMVHFKQHMQNQSDSGPIDLTVNILTMGYWPTYTPME
  VHLTPEMIKLQEVFKAFYLGKHSGRKLQWQTTLGHAVLKAEFKEGKKEFQVSLFQTLVLL
  MFNEGDGFSFEEIKMATGIEDSELRRTLQSLACGKARVLIKSPKGKEVEDGDKFIFNGEF
  KHKLFRIKINQIQMKETVEEQVSTTERVFQDRQYQIDAAIVRIMKMRKTLGHNLLVSELY
  NQLKFPVKPGDLKKRIESLIDRDYMERDKDNPNQYHYVA
• Function: Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. DCX(DET1-COP1) directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of XPC. DCX(DDB2) ubiquitinates histones H3-H4 and is required for efficient histone deposition during replication-coupled (H3.1) and replication-independent (H3.3) nucleosome assembly, probably by facilitating the transfer of H3 from ASF1A/ASF1B to other chaperones involved in histone deposition. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of p53/TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(DTL) directs autoubiquitination of DTL. In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip. Is involved in ubiquitination of HOXA9. The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1. A number of DCX complexes (containing either TRPC4AP or DCAF12 as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The DCX(AMBRA1) complex is a master regulator of the transition from G1 to S cell phase by mediating ubiquitination of phosphorylated cyclin-D (CCND1, CCND2 and CCND3). The DCX(AMBRA1) complex also acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes. With CUL4B, contributes to ribosome biogenesis.
• Uniprot ID: CUL4A_HUMAN
• Ensembl ID: ENSG00000139842
• HGNC ID: HGNC:2554

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter AQueous One Solution Cell Proliferation Assay
• Mechanism Description: H19 LncRNA plays a leading role in breast cancer chemoresistance, mediated mainly through a H19-CUL4A-ABCB1/MDR1 pathway. H19 overexpression was contributed to cancer cell resistance to anthracyclines and paclitaxel.

Lenalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Multiple myeloma [2]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Lenalidomide
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Thalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Multiple myeloma [2]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Thalidomide
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; hsa04151
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Multiple myeloma [ICD-11: 2A83]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bone marrow
• The Specified Disease: Multiple myeloma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.87E-01; Fold-change: 7.20E-02; Z-score: 2.96E-01
• The Studied Tissue: Peripheral blood
• The Specified Disease: Multiple myeloma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.94E-01; Fold-change: 2.28E-02; Z-score: 8.75E-02

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.15E-67; Fold-change: 5.31E-01; Z-score: 1.40E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.19E-07; Fold-change: 3.61E-01; Z-score: 8.61E-01

References

• Ref 1: LncRNA H19 is a major mediator of doxorubicin chemoresistance in breast cancer cells through a cullin4A-MDR1 pathway. Oncotarget. 2017 Sep 21;8(54):91990-92003. doi: 10.18632/oncotarget.21121. eCollection 2017 Nov 3.
• Ref 2: Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood. 2016 Sep 29;128(13):1735-44. doi: 10.1182/blood-2016-06-723007. Epub 2016 Aug 11.