mardi 15 novembre 2011

Mutated genes in cancer (31) – TP53




TP53

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery):7157 or TP¨53
● Ensembl (http://www.ensembl.org/index.html): ENSG00000141510
● UniProt (http://www.uniprot.org/): P04637
● OMIM (http://www.ncbi.nlm.nih.gov/omim):  191170
● GeneCards (http://www.genecards.org/): TP53
● HGNC (http://www.genenames.org/): 11998 or TP53

Gene locus:

17p13.1

Protein name:

Tumor protein p53

Protein Size:

393 amino acids; about 44 kDa

Function:

P53, the protein encoded by TP53, acts as a tumor suppressor in many tumor types; it responds to diverse cellular stresses (DNA damage, hypoxia, nucleotide pool depletion, viral infection, oncogene activation) to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. The type of effect is depending on the physiological circumstances and on the cell type. P53 is involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process.  p53 is expressed at low level in normal cells and at a high level in a variety of transformed cell lines, where it's believed to contribute to transformation and malignancy.

Mutants of p53 that frequently occur in a number of different human cancers fail to bind the p53 consensus DNA binding site, and hence cause the loss of tumor suppressor activity. Alterations of this gene occur not only as somatic mutations in human malignancies, but also as germline mutations in some cancer-prone families with Li-Fraumeni syndrome. Multiple p53 variants due to alternative promoters and multiple alternative splicing have been found. These variants encode distinct isoforms, which can regulate p53 transcriptional activity.

Cancer-related alterations:

Germline TP53 alterations may be a cause of Li-Fraumeni (LFS) or Li-Fraumeni-like (LFL) syndromes. LFS is an autosomal dominant familial cancer syndrome that in its classic form is defined as follows: a person diagnosed with sarcoma before age 45 with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. LFL is characterized by: a person diagnosed with any childhood cancer, sarcoma, brain tumor, or adrenal cortical tumor before age 45 with a first-degree or second-degree relative diagnosed with a typical LFS cancer (sarcoma, breast cancer, brain cancer, adrenal cortical tumor, or leukemia) at any age and another first-degree or second-degree relative diagnosed with any cancer before age 60. Germline mutation of TP53 is found in about 70% of LFS and 50% of LFL cases. In a few cases of LFS/LFL families free of TP53 mutations, germline mutations in genes connected to the p53 pathway have been found: CHEK2, PTEN, CDKN2A (see these genes).
In LFS/LFL families affected patients develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers.
Of note, germinal mutations of P53 have also been found in families where the criteria for LFS or LFL were not reached.

Somatic TP53 mutations are observed in about 50% of human cancers, and the non-mutated allele is generally lost. The frequency and the type of mutation may vary from one tumor type to another. Indeed, somatic TP53 mutations are frequent in most human cancers, ranging from 3% (in cervical cancer, for instance) to 70% depending on the type, stage and etiology of tumors.
Most mutations are “missense” (75%) and other include “non-sense” (7.5%), deletions, insertions or splicing mutations (17.5%). There are some hot spots for mutations at CpG dinucleotides at codon positions 175, 248, 273 and 282, thus in the specific DNA binding domain. TP53 gene mutation is a marker of bad prognosis in a number of cancers, such as breast cancer. Specific mutation spectra are observed in lung, liver and skin cancer that are related to specific carcinogen exposure (tobacco smoke, aflatoxin and UV respectively).

In hematological malignancies, TP53 is genetically altered in less than 5% of acute lymphoblastic leukemia (ALL), but in 60-80% of Hodgkin disease.
In skin cancers, TP53 is mutated in 40% of basal cell carcinomas and squamous cell carcinomas (SCC) while mutations are infrequent in malignant melanoma. The pattern of TP53 mutation in skin cancer is highly related to UV exposure with a high frequency of CC->TT and C->T transitions and specific hot spots at codons 196 and 278.

In breast cancers, the prevalence of mutations is higher in large size, high grade and estrogen receptor negative tumors. It is also higher in BRCA1-related tumors.

In lung cancers, most TP53 mutations are linked to exposure to tobacco smoke.

TP53 alterations are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.

Therapy:

Various approaches: reactivation of mutant p53 (PhiKan083, PRIMA-1, CP-31398), p53 stabilization (nutlins, MI-219, tenovin, RITA), p53 gene therapy, p53-based immunotherapy (for a review, see Suzuki & Matsubara 2011).

References (open access):

Recent Advances in p53 Research and Cancer Treatment. Suzuki K, Matsubara H. J Biomed Biotechnol. 2011;2011:978312.

One function--multiple mechanisms: the manifold activities of p53 as a transcriptional repressor. Böhlig L, Rother K. J Biomed Biotechnol. 2011;2011:464916.

p53 and its mutants in tumor cell migration and invasion. Muller PA, Vousden KH, Norman JC. J Cell Biol. 2011 Jan 24;192(2):209-18.



1 commentaire:

  1. Hello,

    Thanks for providing these useful tips over here. Mutations is a key regulatory genes alter the behavior of cells and can potentially lead to the unregulated growth seen in cancer, it seems as if the transition from a normal, healthy cell to a cancer cell is step wise progression that requires genetic changes in several different oncogenes and tumor suppressors...

    Apoptosis Detection

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