What is so memorable about CREBBP?

(RSTS; RTS, CBP CBP/MOZ FUSION GENE, CREB-binding protein)

Where is it found?

What exactly does “BP” mean

• Binding protien

• What is a coactivator and what is its role?

• Does it perform one function (interaction) or does it perform many? pg224 of book

• http://www.ebi.ac.uk/intact/search/do/search?searchString=EBI-81215&filter=ac&searchClass=Protein&view=partner&filter=ac

What is its function and where is it found? Gene Ontology

Gene Ontologies

Normalized expression distribution for tissue type Top ten

Ontology Annotation Evidence Source

Molecular Function

Histone acetyltransferase activity IEA GOA/IPI

Signal transducer activity TAS GOA/IPI

Transcription coactivator activity IEA GOA/IPI

Transcription coactivator activity IPI GOA/IPI

Protein binding IPI GOA/IPI

Transcription factor activity TAS GOA/IPI

Transferase activity IEA GOA/IPI

Zinc ion binding IEA GOA/IPI

Biological Process

Regulation of transcription, DNA-dependent IEA GOA/IPI

Regulation of transcription, DNA-dependent TAS GOA/IPI

Response to hypoxia TAS GOA/IPI

Homeostasis NAS GOA/IPI

Signal transduction NAS GOA/IPI

Protein complex assembly TAS GOA/IPI

Cellular ComponentCytoplasm TAS GOA/IPI

Nucleus IEA GOA/IPI

Nucleus TAS GOA/IPI

TissueNormalized

Expression (%)Cluster Clones :

Tissue clones

posterior tongue (pooled): 22.02 2:473

Brain: 10.61 1:491

liposarcoma: 5.31 1:980

lymph: 3.84 15:20369

Trabecular meshwork: 3.65 2:2854

metastatic prostate bone lesion: 3.24 2:3214

fibrotheoma: 2.51 3:6234

prostata: 2.21 1:2355

salivary gland: 2.07 1:2521

myeloid cells, 18 pooled CML cases, BCR/ABL rearrangement positive, includes both chronic phase and myeloid blast crisis:

2.01 1:2589

What makes up the coding sequence?

It is made of 32 exons and 31 introns. The mRNA itself is 8.7 kb, 7.3 of that is coding!

Enough about its genome, lets talk protein!

• The protein is made of 2442 amino acids and is 265 kDa!

• That’s nice, but what does it look like?

Seven Different Domains

BromodomainZinc finger ZZ type TAZ zinc

finger

KIX Two Domains of unknown functions (interact with other pfams

Creb binding

So now that I know what its made of and where its found…. What does it

do?• Mediates cAMP-gene regulation by

binding specifically to phosphorylated CREB protein. CREBBP, as coactivator, augments the activity of phosphorylated CREB to activate transcription of cAMP-responsive genes.

• What do we know about cAMP and memory? pg.223

Sounds nice, but what does that have to do with memory?

• http://www.dnai.org/text/mediashowcase/index2.html?id=483• CREB turns on other genes to store in long term memory. • Switched on to create new connections between nerve cells• Turning off and on genes by the act of remembering.• In other words, CREB is a gene that mediates long-term memory. It

acts as a master gene that turns on other genes, assisted by CREBBP

• Evidence for this function- studies on CREBBP transgenic mice suggests that competition for CBP plays an important role in regulating gene expression during cell growth. CREBBP and p300 function as transcriptional coactivators in the regulation of gene expression through various signal transduction pathways

Diseases associated with CREBBP

• Rubinstein-Taybi syndrome

• Result of germline mutation of CREBBP

• myeloid leukemias• MLL translocations involving the CREBBP gene have primarily been reported in treatment-related acute myeloid lukemia after chemotherapy for other primary malignancies using topoisomerase II inhibitors.

ReferencesRidley, Matt. "Chromosome 16, Memory." Genome, The Autobiography of a species in

     23 Chapters. New York: Harper Perennial, 1999. 219-230.

http://www.dsi.univ-paris5.fr/genatlas/fiche.php?symbol=CREBBP (slide 2,6)

http://atlasgeneticsoncology.org/Genes/CBPID42.html (slide 10)

http://genome-www5.stanford.edu/cgi-bin/source/sourceResult?criteria=CREBBP&choice=Gene&option=Symbol&organism=Hs

(slide 4, 8)http://www.ihop-net.org/UniPub/iHOP/gismo/87420.html (slide and 9)

http://www.ncbi.nlm.nih.gov/genome/guide/human/ (slide 1)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=1387 (slide 5)

http://www.ebi.ac.uk/intact/search/do/search?searchString=EBI-81215&filter=ac&searchClass=Protein&view=partner&filter=ac (slide 3)

http://www.sanger.ac.uk/cgi-bin/Pfam/qquerypfam.pl?terms=crebbp (slide 7)