Retinoblastoma protein

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RB-1
RB-1
Ribbon model of domain A from RB (amino acids 378-562) according to PDB  1AD6

Existing structural data : 1ad6 , 1gh6 , 1gux , 1o9k , 2aze

Properties of human protein
Mass / length primary structure 928 amino acids
Identifier
Gene names RB1  ; OSRC; RB
External IDs
Occurrence
Homology family RB
Parent taxon Euteleostomi
Orthologue
human mouse
Entrez 5925 19645
Ensemble ENSG00000139687 ENSMUSG00000022105
UniProt P06400 Q3UFM7
Refseq (mRNA) NM_000321 NM_009029
Refseq (protein) NP_000312 NP_033055
Gene locus Chr 13: 47.78 - 47.95 Mb Chr 14: 72.06 - 72.06 Mb
PubMed search 5925 19645

The retinoblastoma protein (pRb, Rb) is a tumor suppressor - protein , which in many tumors has an impaired function. A very well-studied function of pRb is to slow down cell growth by slowing the flow of the cell cycle. pRb belongs to the so-called pocket protein family . Its members have a molecular pocket for binding to other proteins. When oncogene products, such as those produced in cells infected by human papillomaviruses , bind to pRb, this can lead to cancer.

Name and genetics

In humans, pRb is encoded by a gene in the region of chromosome 13 gene locus q14.1-q14.2. When both alleles of the gene are mutated, affected patients develop retinoblastoma , hence the name. It is not yet clear why mutations in a gene that regulates the cell cycle in the entire human organism can lead to an eye tumor. There are two forms of retinoblastoma: a bilateral familial and a unilateral sporadic variant. In the former case, the risk of developing further tumors is six times greater than the average. This fact illustrates the concept of the Knudson hypothesis . This states that one allele of a tumor suppressor gene is sufficient to maintain the function (the mutated gene is recessive) and therefore both must be mutated in order for the tumor phenotype to be visible. In the familial form of retinoblastoma, a mutated allele is inherited with a healthy allele. Then, when another RB mutation occurs in a cell, all of the Rb proteins in the cell are inoperable in terms of their ability to control the cell cycle. This allows the cells to divide in an uncontrolled manner. This is an important step in the development of cancer. As a result, the risk that tumors will develop in all body cells increases linearly. No direct mutation of the RB gene is required, a loss of heterozygosity (LOH), which is often found in tumor cells, is sufficient.

In patients with the sporadic form of retinoblastoma, a new mutation of both alleles is necessary. This explains why those affected do not have an increased risk of developing further tumors, since there are two functional RB alleles in their body cells. The tumor incidence in patients with a sporadic form of retinoblastoma does not follow quadratic kinetics. This would be expected if the mutation of the two alleles occurred independently of one another. In fact, the risk of developing further tumors follows polynomial kinetics, which indicates that the mutation of the second allele can be triggered by an LOH process in the cell concerned with a mutated RB gene and therefore occurs more frequently than when this mutation would be independent of the first event.

Cell cycle regulation

pRB protects the cell from replicating damaged DNA by preventing the cell from cycling through the G1 phase to the S phase. The RB protein binds and inhibits the activity of transcription factors of the E2F family, which consist of heterodimers of the E2F protein and the DP protein.

The transcription- activating complex of the “E2 promoter-binding-protein-dimerization partners” (E2F-DP) can push a cell into the S phase. As long as E2F-DP is inactivated, the cell remains in the G1 phase. When pRB binds to E2F, the complex acts like a growth suppressor and hinders progression through the cell cycle. The pRb-E2F / DP complex also binds a histone deacetylase (HDAC) protein to the chromatin and thus additionally suppresses DNA synthesis .

Activation and inactivation of pRb

The RB protein is activated by dephosphorylation and thus exercises its function as a tumor suppressor by having a regulatory influence on the course of the cell cycle . Phosphorylation inactivates the RB protein. During the transition from the M to the G1 phase, pRB is increasingly dephosphorylated by PP1, and so returns to its growth-inhibiting, hypophosphorylated state.

In the G1 phase, more precisely at the restriction point (R point) of the cell cycle, the retinoblastoma protein is first phosphorylated by cyclin D and the cyclin-dependent kinase (CDK) 4/6. The further passage of the cell cycle is guaranteed by the phosphorylation of the pRb. The protein thereby loses its inhibitory ability. The phosphorylation of the pRB is started by the cyclin D / CDK4,6 and continued by the cyclin E / CDK2. pRB remains phosphorylated during the S, G2 and M phases. Phosphorylation of pRB allows the E2F-DP complex to dissociate from pRB, thereby activating this complex. When unbound, E2F activates the cyclins E and A, which drive the cell through the cell cycle by activating the cyclin-dependent kinase and the proliferating cell nuclear antigen PCNA . This speeds up DNA replication and DNA repair by attaching DNA polymerases to the DNA.

See also

Individual evidence

  1. ↑ AL Murphree, WF Benedict: Retinoblastoma: clues to human oncogenesis. In: Science. Volume 223, Number 4640, March 1984, pp. 1028-1033, PMID 6320372 (Review).
  2. ↑ a b M. Korenjak, A. Brehm: E2F-Rb complexes regulating transcription of genes important for differentiation and development. In: Current opinion in genetics & development. Volume 15, number 5, October 2005, pp. 520-527, doi : 10.1016 / j.gde.2005.07.001 , PMID 16081278 (review).
  3. ↑ a b c d e f K. Münger, PM Howley: Human papillomavirus immortalization and transformation functions. In: Virus research. Volume 89, Number 2, November 2002, pp. 213-228, PMID 12445661 (review).
  4. ^ RA Kleinerman, MA Tucker et al. a .: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. In: Journal of clinical oncology. Volume 23, number 10, April 2005, pp. 2272-2279, doi : 10.1200 / JCO.2005.05.054 , PMID 15800318 .
  5. ^ AG Knudson: Mutation and cancer: statistical study of retinoblastoma. In: Proceedings of the National Academy of Sciences . Volume 68, Number 4, April 1971, pp. 820-823, PMID 5279523 , PMC 389051 (free full text).
  6. ↑ a b c d S. K. Das, T. Hashimoto u. a .: Fucoxanthin induces cell cycle arrest at G0 / G1 phase in human colon carcinoma cells through up-regulation of p21WAF1 / Cip1. In: Biochimica et Biophysica Acta . Volume 1726, Number 3, November 2005, pp. 328-335, doi : 10.1016 / j.bbagen.2005.09.007 , PMID 16236452 .
  7. ↑ CL Wu, LR Zukerberg u. a .: In vivo association of E2F and DP family proteins. In: Molecular and cellular biology. Volume 15, Number 5, May 1995, pp. 2536-2546, PMID 7739537 , PMC 230484 (free full text).
  8. ↑ a b J. O. Funk, S. Waga u. a .: Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein. In: Genes & development. Volume 11, Number 16, August 1997, pp. 2090-2100, PMID 9284048 , PMC 316456 (free full text).
  9. ↑ a b L. De Veylder, J. Joubès, D. Inzé: Plant cell cycle transitions. In: Current opinion in plant biology. Volume 6, Number 6, December 2003, pp. 536-543, PMID 14611951 (review).
  10. ↑ SM de Jager, S. Maughan et al. a .: The developmental context of cell-cycle control in plants. In: Seminars in cell & developmental biology. Volume 16, Number 3, June 2005, pp. 385-396, doi : 10.1016 / j.semcdb.2005.02.004 , PMID 15840447 (review).
  11. ^ A b R. J. Greenblatt: Human papillomaviruses: Diseases, diagnosis, and a possible vaccine. In: Clinical Microbiology Newsletter. 27, 2005, pp. 139-145, doi : 10.1016 / j.clinmicnews.2005.09.001 .
  12. ↑ SH Sinal, CR Woods: Human papillomavirus infections of the genital and respiratory tracts in young children. In: Seminars in pediatric infectious diseases. Volume 16, Number 4, October 2005, pp. 306-316, doi : 10.1053 / j.spid.2005.06.010 , PMID 16210110 (review).
  13. ↑ M. Vietri, M. Bianchi u. a .: Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb. In: Cancer Cell International . Volume 6, 2006, p. 3, doi : 10.1186 / 1475-2867-6-3 , PMID 16466572 , PMC 1382259 (free full text).
  14. ↑ Bartkova J., Grøn B., Dabelsteen E., and Bartek J .: Cell-cycle regulatory proteins in human wound healing . In: Archives of Oral Biology , 48 (2): 125-132. (2003) PMID 12642231 .

literature

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  • L. Zheng, WH Lee: Retinoblastoma tumor suppressor and genome stability. In: Advances in Cancer Research . Vol. 85, 2002, pp. 13-50, PMID 12374284 (review).
  • M. Classon M, E. Harlow : The retinoblastoma tumor suppressor in development and cancer. In: Nature Reviews Cancer . Volume 2, Number 12, December 2002, pp. 910-917, doi : 10.1038 / nrc950 , PMID 12459729 (review).
  • H. Lai, F. Ma, S. Lai: Identification of the novel role of pRB in eye cancer. In: Journal of cellular biochemistry. Volume 88, Number 1, January 2003, pp. 121-127, doi : 10.1002 / jcb.10283 , PMID 12461781 (review).
  • K. Simin, H. Wu et al. a .: pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. In: PLoS biology. Volume 2, number 2, February 2004, p. E22, doi : 10.1371 / journal.pbio.0020022 , PMID 14966529 , PMC 340938 (free full text) (review).
  • DR Lohmann, BL Gallie: Retinoblastoma: revisiting the model prototype of inherited cancer. In: American journal of medical genetics. Part C, Seminars in medical genetics. Volume 129C, Number 1, August 2004, pp. 23-28, doi : 10.1002 / ajmg.c.30024 , PMID 15264269 (review).
  • NK Clemo, NJ Arhel et al. a .: The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumor cell survival. In: Biochemical Society transactions. Volume 33, Pt 4 August 2005, pp. 676-678, doi : 10.1042 / BST0330676 , PMID 16042572 (review).
  • M. Rodríguez-Cruz, M. del Prado, M. Salcedo: [Genomic retinoblastoma perspectives: implications of tumor supressor gene RB1]. In: Revista de investigación clínica; organo del Hospital de Enfermedades de la Nutrición. Volume 57, Number 4, 2005 Jul-Aug, pp. 572-581, PMID 16315642 (review).
  • ES Knudsen, KE Knudsen: Retinoblastoma tumor suppressor: where cancer meets the cell cycle. In: Experimental biology and medicine (Maywood, NJ). Volume 231, Number 7, July 2006, pp. 1271-1281, PMID 16816134 (review).

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