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p73 - A Structural and Functional Homolog of p53- Antibodies
p53, the most frequent target of genetic alterations in human cancer, is one of the most widely studied tumor suppressor gene. The most important activities of p53 are its cellular growth arrest and induction of programmed cell death (apoptosis). Human p53 is a single polypeptide chain of 393 AA. It has three well-defined functional domains: An N-terminal acidic transactivation domain (TAD), a central DNA-binding domain (DBD), and a C-terminal homo-oligomerization domain (OD). All three domains are important for interaction with target genes. A great majority of tumor-associated missense mutations occur within the DBD and the mutant protein fails to regulate p53 target genes. Posttranslational modifications of p53 (phosphorylation and acetylation) have been implicated in its physiological role. p53 has at least 4 phosphorylation sites at the N-terminus with Ser15 as an important site in response to DNA damage and a target of the ATM and DNA PK proteins. There are three potential sites within the C-terminus of p53 that may affect its DNA-binding ability. p53 also serve as a substrate for various histone acetylases to enhance it transcriptional activity. p63 has been identified as structural and functional homolog of p53. The p63 gene encodes several isoforms: p63alpha (also designated p51B or KET), p63beta and p63gamma (p51A), as well as corresponding TA* p63 isoforms, containing p53 transactivation domains. LNp63 isoforms lack the transactivation domain and inhibits transactivation by p53 and p63. p73 appears to shares many structural and functional features of p53. Human p73 gene encodes two distinct polypeptides: The p73 long form (636 AA, termed p73alpha) and the short form (499 AA; termed p73beta). The short form arises through alternative splicing of the p73. With the exception of C-terminal 5 AA, p73beta is identical to p73alpha. Both p73a and p73b transcripts were detected all human tissues. The endogenous p73a protein has also been detected in cell extracts of HT-29, IMR-32, and SK-N-SH cells. The DBD domains of p53 and p73 show a 63% homology with a remarkable conservation of critical residues that are known to be important for the binding of p53 to target genes or proper folding of p53. A significant homology also exists in the TAD and OD of p53 and p73. The C-terminal domain (364-393) of p53 and p73 are quite distinct. p73 has been mapped to human chromosome 1p36, a region that is frequently deleted in variety of human cancers including neuroblastoma, colon cancer, and breast cancer.
M=
Mouse; R=Rat; H=Human; Rb=Rabbit; B=Bovine; CT= near
C-terminus; NT=near N-terminus; I=Middle of protein; CL=Cytoplasmic
loop; EC=Extracellular domain; IC=Intracellular domain;
*
w=wilde type; m=mutant p53 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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