Retinoblastoma is a tumor that arises in the retina and accounts for about three percent of cancer in children below the age of fifteen years. (Donaldson, et. al. 1993) Retinoblastoma occurs most frequently in children and has an annual incidence of approximately four children per million. Ninety five percent of cases are diagnosed before the age of five. (Shields, et. al. 1991)Retinoblastoma may be manifested unilaterally(one eye), or bilaterally(both eyes). There are two classes of retinoblastoma. The first class is germline retinoblastoma. The other class of retinoblastoma is the sporadic form of the disease.Most unilateral disease is sporadic whereas all bilateral disease cases are germline.Phenotypically, the majority of children with retinoblastoma have a white pupil instead of the normal black pupil. Other signs of retinoblastoma include red eye, poor vision, and inflammation of tissue surrounding the eye.
The gene for retinoblastoma lies on chromosome 13 within the q14 band (long arm) and usually is a result of a deletion within this band. Results vary with mutations in the Rb gene. This occurs when the mutated allele (Rb-) is inherited from one parent and a normal allele (Rb+) from the other parent. Tumors arise when a spontaneous mutation occurs in the normal allele rendering both copies of the gene nonfunctional. This form occurs when two normal alleles are inherited and both alleles spontaneously mutate. As could be expected, germline forms are much more common because the chances of two autosomal mutations is much less likely. (Lodish, et. al. 1999)
The retinoblastoma gene, denoted Rb, is a gene that codes for the Rb protein, which functions as a tumor suppressor. Normally, Rb protein is bound to the transcription factor E2F keeping it in the inactive state. When the cell is in mid G1 of the cell cycle, induced expression for Cyclin D, Cdk4, Cdk 6, and the transcription factor E2F occurs in order to prepare the cell for mitosis. The cyclin/Cdk complexes initiate the phosphorylation of Rb, which releases the protein from E2F. Phosphorylation occurs at the amino acid serine and the location of such phosphorylation sites is highlighted in RED in the amino acid sequence.(Swiss Prot) Subsequently, E2F is converted to the active form.E2F is then able to stimulate its own synthesis and that of Cdk2 and cyclin E. These particular Cdk/Cyclin complexes further stimulate the phosphorylation of Rb allowing more E2F activity. After mitosis, the level of Cdk/Cyclin complexes falls, leading to the dephosphorylation of Rb. As the protein is dephosphoylated, it again combines with E2F rendering it inactive. When there is a defective Rb protein, E2F is unregulating. Consequently, cell division becomes continuous resulting in the growth of a tumor.
The Rb gene consists of a total of 180,388 base pairs which includes 23 exons. However, upon processing, the messenger RNA consists of only 4740 base pairs. Once synthesized by ribosomes, the Rb protein has 928 amino acids with a molecular weight of 106159 Daltons. The start codon (RED) starts 343 base pairs into the mRNA and the stop codon (BLUE)appears at base number 3127. Another interesting feature of this gene is the repeated regions found in the code. One of these regions is between base pairs 123912-125501.(OMIM)Additionally, other mammals also have Rb1, even though it may be found on other chromosomes.
Retinoblastoma mRNA
BASE COUNT 1508 a 887 c 862 g 1483 t
ORIGIN
1 ttccggtttt tctcagggga cgttgaaatt atttttgtaa cgggagtcgg gagaggacgg
61 ggcgtgcccc gcgtgcgcgc gcgtcgtcct ccccggcgct cctccacagc tcgctggctc
121 ccgccgcgga aaggcgtcat gccgcccaaa accccccgaa aaacggccgc caccgccgcc
181 gctgccgccg cggaaccccc ggcaccgccg ccgccgcccc ctcctgagga ggacccagag
241 caggacagcg gcccggagga cctgcctctc gtcaggcttg agtttgaaga aacagaagaa
301 cctgatttta ctgcattatg tcagaaatta aagataccag
atcATGtcag agagagagct
361 tggttaactt gggagaaagt ttcatctgtg gatggagtat tgggaggtta tattcaaaag
421 aaaaaggaac tgtggggaat ctgtatcttt attgcacgag ttgacctaga tgagatgtcg
481 ttcactttac tgagctacag aaaaacatac gaaatcagtg tccataaatt ctttaactta
541 ctaaaagaaa ttgataccag taccaaagtt gataatgcta tgtcaagact gttgaagaag
601 tatgatgtat tgtttgcact cttcagcaaa ttggaaagga catgtgaact tatatatttg
661 acacaaccca gcagttcgat atctactgaa ataaattctg cattggtgct aaaagtttct
721 tggatcacat ttttattagc taaaggggaa gtattacaaa tggaagatga tctggtgatt
781 tcatttcagt taatgctatg tgtccttgac tattttatta aactctcacc tcccatgttg
841 ctcaaagaac catataaaac agctgttata cccattaatg gttcacctcg aacacccagg
901 cgaggtcaga acaggagtgc acggatagca aaacaactag aaaatgatac aagaattatt
961 gaagttctct gtaaagaaca tgaatgtaat atagatgagg tgaaaaatgt ttatttcaaa
1021 aattttatac cttttatgaa ttctcttgga cttgtaacat ctaatggact tccagaggtt
1081 gaaaatcttt ctaaacgata cgaagaaatt tatcttaaaa ataaagatct agatcgaaga
1141 ttatttttgg atcatgataa aactcttcag actgattcta tagacagttt tgaaacacag
1201 agaacaccac gaaaaagtaa ccttgatgaa gaggtgaata taattcctcc acacactcca
1261 gttaggactg ttatgaacac tatccaacaa ttaatgatga ttttaaattc tgcaagtgat
1321 caaccttcag aaaatctgat ttcctatttt aacaactgca cagtgaatcc aaaagaaagt
1381 atactgaaaa gagtgaagga tataggatac atctttaaag agaaatttgc taaagctgtg
1441 ggacagggtt gtgtcgaaat tggatcacag cgatacaaac ttggagttcg cttgtattac
1501 cgagtaatgg aatccatgct taaatcagaa gaagaacgat tatccattca aaattttagc
1561 aaacttctga atgacaacat ttttcatatg tctttattgg cgtgcgctct tgaggttgta
1621 atggccacat atagcagaag tacatctcag aatcttgatt ctggaacaga tttgtctttc
1681 ccatggattc tgaatgtgct taatttaaaa gcctttgatt tttacaaagt gatcgaaagt
1741 tttatcaaag cagaaggcaa cttgacaaga gaaatgataa aacatttaga acgatgtgaa
1801 catcgaatca tggaatccct tgcatggctc tcagattcac ctttatttga tcttattaaa
1861 caatcaaagg accgagaagg accaactgat caccttgaat ctgcttgtcc tcttaatctt
1921 cctctccaga ataatcacac tgcagcagat atgtatcttt ctcctgtaag atctccaaag
1981 aaaaaaggtt caactacgcg tgtaaattct actgcaaatg cagagacaca agcaacctca
2041 gccttccaga cccagaagcc attgaaatct acctctcttt cactgtttta taaaaaagtg
2101 tatcggctag cctatctccg gctaaataca ctttgtgaac gccttctgtc tgagcaccca
2161 gaattagaac atatcatctg gacccttttc cagcacaccc tgcagaatga gtatgaactc
2221 atgagagaca ggcatttgga ccaaattatg atgtgttcca tgtatggcat atgcaaagtg
2281 aagaatatag accttaaatt caaaatcatt gtaacagcat acaaggatct tcctcatgct
2341 gttcaggaga cattcaaacg tgttttgatc aaagaagagg agtatgattc tattatagta
2401 ttctataact cggtcttcat gcagagactg aaaacaaata ttttgcagta tgcttccacc
2461 aggcccccta ccttgtcacc aatacctcac attcctcgaa gcccttacaa gtttcctagt
2521 tcacccttac ggattcctgg agggaacatc tatatttcac ccctgaagag tccatataaa
2581 atttcagaag gtctgccaac accaacaaaa atgactccaa gatcaagaat cttagtatca
2641 attggtgaat cattcgggac ttctgagaag ttccagaaaa taaatcagat ggtatgtaac
2701 agcgaccgtg tgctcaaaag aagtgctgaa ggaagcaacc ctcctaaacc actgaaaaaa
2761 ctacgctttg atattgaagg atcagatgaa gcagatggaa gtaaacatct cccaggagag
2821 tccaaatttc agcagaaact ggcagaaatg acttctactc gaacacgaat gcaaaagcag
2881 aaaatgaatg atagcatgga tacctcaaac aaggaagaga aatgaggatc tcaggacctt
2941 ggtggacact gtgtacacct ctggattcat tgtctctcac agatgtgact gtataacttt
3001 cccaggttct gtttatggcc acatttaata tcttcagctc tttttgtgga tataaaatgt
3061 gcagatgcaa ttgtttgggt gagtcctaag ccacttgaaa tgttagtcat tgttatttat
3121
acaagatTGA aaatcttgtg taaatcctgc catttaaaaa
gttgtagcag attgtttcct
3181 cttccaaagt aaaattgctg tgctttatgg atagtaagaa tggccctaga gtgggagtcc
3241 tgataaccca ggcctgtctg actactttgc cttcttttgt agcatatagg tgatgtttgc
3301 tcttgttttt attaatttat atgtatattt ttttaattta acatgaacac ccttagaaaa
3361 tgtgtcctat ctatcttcca aatgcaattt gattgactgc ccattcacca aaattatcct
3421 gaactcttct gcaaaaatgg atattattag aaattagaaa aaaattacta attttacaca
3481 ttagatttta ttttactatt ggaatctgat atactgtgtg cttgttttat aaaattttgc
3541 ttttaattaa ataaaagctg gaagcaaagt ataaccatat gatactatca tactactgaa
3601 acagatttca tacctcagaa tgtaaaagaa cttactgatt attttcttca tccaacttat
3661 gtttttaaat gaggattatt gatagtactc ttggttttta taccattcag atcactgaat
3721 ttataaagta cccatctagt acttgaaaaa gtaaagtgtt ctgccagatc ttaggtatag
3781 aggaccctaa cacagtatat cccaagtgca ctttctaatg tttctgggtc ctgaagaatt
3841 aagatacaaa ttaattttac tccataaaca gactgttaat tataggagcc ttaatttttt
3901 tttcatagag atttgtctaa ttgcatctca aaattattct gccctcctta atttgggaag
3961 gtttgtgttt tctctggaat ggtacatgtc ttccatgtat cttttgaact ggcaattgtc
4021 tatttatctt ttattttttt aagtcagtat ggtctaacac tggcatgttc aaagccacat
4081 tatttctagt ccaaaattac aagtaatcaa gggtcattat gggttaggca ttaatgtttc
4141 tatctgattt tgtgcaaaag cttcaaatta aaacagctgc attagaaaaa gaggcgcttc
4201 tcccctcccc tacacctaaa ggtgtattta aactatcttg tgtgattaac ttatttagag
4261 atgctgtaac ttaaaatagg ggatatttaa ggtagcttca gctagctttt aggaaaatca
4321 ctttgtctaa ctcagaatta tttttaaaaa gaaatctggt cttgttagaa aacaaaattt
4381 tattttgtgc tcatttaagt ttcaaactta ctattttgac agttattttg ataacaatga
4441 cactagaaaa cttgactcca tttcatcatt gtttctgcat gaatatcata caaatcagtt
4501 agtttttagg tcaagggctt actatttctg ggtcttttgc tactaagttc acattagaat
4561 tagtgccaga attttaggaa cttcagagat cgtgtattga gatttcttaa ataatgcttc
4621 agatattatt gctttattgc ttttttgtat tggttaaaac tgtacattta aaattgctat
4681 gttactattt tctacaatta atagtttgtc tattttaaaa taaattagtt gttaagagtc
Retinoblastoma protein: RR1. Amino acid Sequence |
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