Author: Rajesh Kumar

Wild type p53 is associated with childhood tumours [Ref: Bobbin’s 8^th/e p. 290, 291, 292]

Wild type 53 is the normal (non mutated form of p53).

• The normal p53 gene is a tumour suppressor gene that prevents the development of tumours.
• When wild/normal p53 gene undergoes some mutation, it is called the mutant p53 gene.
• Mutant p53 gene is associated with various human cancers.

– A little over 50% human tumours contain mutation in this gene.

– Homozygous loss of p53 occurs in virtually every type of cancer including carcinomas of the lung, colon and breast.

p53 Guardian of genome

• p53 gene is located on chromosome 17Q.
• It is a tumour suppressor gene.
• “p53 acts as a molecular policemean that prevents the propagation of genetically damaged cell”.

– p53 gene product i.e., p53 protein is a DNA binding protein in the nucleus, when called into action, it controls the transcription of several other genes.

• The major functional activities of the p53 protein are: ?

Activation of temporary cell cycle arrest (quiescence)

–p53 induces transcription of p21°, a CDK inhibitor.

– p21 inhibit cyclin D-CDK-4 ^e complex leading to arrest of cell cycle late in G1 phase. – This allows time for DNA repair (1.

DNA repair

p53 helps in DNA repair not only by allowing time for DNA repair but also by directly inducing the transcription of GADD 45^Q (growth arrest and DNA damage).

– GADD 45 encodes a protein that is involved in DNA repair.

– If DNA damage is repaired successfully, p53 activates MDM 2 which in turn causes degradation of p53. This MDM-2 induced degradation of p53 causes relieve in cell cycle block.

Triggering of programmed cell death

p53 directs the transcription of several pro-apoptotic genes such as BAX and PUMA (approved name BBC3) and induces apoptosis.

Induction of pennanent cell cycle arrest (quiescent)

p53 can also cause permanent cell cycle arrest.

It is characterized by specific changes in morphology and the exact mechanism is not known.

p53

Non mutated wild p53 is asssociated with neoplasm in childhood

p53 acts as a ‘molecular policemen’ that prevents the propagation of genetically damaged cells. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer.

As such, p53 has been described as “the guardian of the genome” because of its role in conserving stability by preventing genome mutation.

Ref: Robbins Pathology, 7th Ed, page 302

The tumor suppressor p53, a protein of apparent MW 53 kDa.

The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13).

When DNA Is damaged, the p53 protein accumulates in cells.

It first arrests the cell cycle (at the G1 phase) to allow the DNA to be repaired before it is replicated.

A cell with damaged DNA that cannot be repaired is directed by p53 to either enter senescence or undergo apoptosis.

In view of these activities, p53 has been called the ‘guardian of the genome’. 

o p53 gene is located on chromosome 17p13 and it is the most common target for genetic alteration in human tumors. A little over 50% human tumors contain mutation in this gene.

o DNA topoisomerase bind tightly to DNA double helix and make transient breaks in both strands.

o Telomerase activity and maintenance of Telomer length are essential for maintenance of relicative potential in tumor cells —> Decrease of telomerase activity cause antitumor effects

o G_IS and G₂M are cell cycle check point and defect in cell cycle check point component is a major cause of genetic instability in cancer cells.

o Genetic mutations associated with breast cancer are of two types‑

(i)      Germline mutations (inherited mutations)

o Involved in familial cases of breast cancer

(ii)    Somatic mutations (acquired mutation)

o Involved in sporadic cases of breast cancer

o Tumour suppressor genes involved in Breast cancer

(i) Genes involved in germline mutations (cause familial Breast Ca)

(a)  BRCA-1 and BRCA-2 –> Causes familial breast and ovary Ca

(b)  p53 —> (Li Fraumeni syndrome) — There is increased susceptibility to Ca breast, colon, leukemia, Sarcomas, brain tumours.

(ii) Genes involved in Somatic mutation (cause spordic breast cancer or primary breast cancer) —-> p53

o So p53 gene is involved in both germline mutation and somatic mutation causing breast cancer. Where as BRCA-1 is involved only in germline mutation

p53; Guardian of genome

o p53 is a tumor suppressor gene.

o p53 gene is located on chromosome 17.

o p53 acts as molecular policeman that prevents the propagation of genetically damage cell.

o p53 gene product, i.e. p53 protein is a DNA binding protein in the nucleus, when called into action, it controls the transcription of several other genes.

o The major functional activities of the p53 protein are cell cycle arrest and initiation of apoptosis in response to DNA damage.

o When there is DNA damage due to irradiation, UV light or mutagenic chemicals, there is rapid increase in p53

levels.

It is mutated form (not non mutated form) of p53 which is associated with increased risk of tumors.

o p53 gene is a tumor suppressor gene and non-mutated form of this gene prevent development of malignancy by :

(i)   Causing cell cycle arrest in late GI phase

(ii)   Inducing apoptosis

(iii)  Helping in DNA repair

o Mutation in p53 gene causes inactivation of p53 gene and abolishen of above function that results in uncontrolled proliferation of cells and malignant transformation.

o Mutation in p53 gene is the most common genetic alteration found in human Cancer.

o The name p53 is in reference to its apparent molecular mass; it runs as a 53 kilodalton (Kda) protein on SDS-page. But based on calculations from its amino acid residues, p53 ‘s mass is actually only 43.7 K Da.

o p53 prevents neoplastic transformation by three interlocking mechanisms : ‑

1.  Activation of temporary cell cycle arrest (quiescence)

o It is considered as the primordial response to DNA damage.

o p53 causes arrest in late GI through p2 I .

o This is temporary arrest that gives the cell “breathing time” to repair DNA damage.

o After DNA repair, cell cycle block is relieved by MDM-3 which degrades p53.

2.  Induction of permanent cell cycle arrest (senescence)

o p53 induced sencence is a permanent cell cycle arrest characterized by specific changes in morphology and gene expression that differentiate it from quiescence (temporary or reversible cycle arrest).

o The mechanisms of senscence is unknown, but involve epigenetic changes that result in the formation of heterochromatin at different loci throughout the genome.

3.  Triggering of programmed cell death

o p53 directs the transcription of several pro-apoptotic genes such as BAX and PUMA (approved name BBC3) and induces apoptosis.

o It has been shown that p53 activates transcription of the mir 34 family of micro RNAs (miRNAs),mir 34a.

o mir34 inhibits translation of anti-apoptotic genes such as BCL2 (there by induce apoptosis) and pro-proliferative genes such as cyclins (there by prevent proliferation) p53 induce apoptosis and prevent proliferation through mir34.

o p 53 is a tumor suppressor gene and it is a proapoptotic factor, i.e. it promotes apoptosis if repair of DNA damage is unsuccessful at G₁ arrest.

o The name p53 is in reference to its apparent molecular mass; it runs as a 53 kilodalton (Kda) protein on SDS-page. But based on calculations from its amino acid residues, p53 ‘s mass is actually only 43.7 K Da.

Ans. is ‘d’ i.e., Non mutated wild p53 is associated with neoplasm in childhood

It is mutated form (not non mutated form) of p53 which is associated with increased risk of tumors.

o p53 gene is a tumor suppressor gene and non-mutated form of this gene prevent development of malignancy by :

(i)       Causing cell cycle arrest in late GI phase

(ii)     Inducing apoptosis

(iii)      Helping in DNA repair

o Mutation in p53 gene causes inactivation of p53 gene and abolishen of above function that results in uncontrolled proliferation of cells and malignant transformation.

o Mutation in p53 gene is the most common genetic alteration found in human Cancer.

o The name p53 is in reference to its apparent molecular mass; it runs as a 53 kilodalton (Kda) protein on SDS-page. But based on calculations from its amino acid residues, p53’s mass is actually only 43.7 K Da.

Ans. is ‘c’ i.e., G₁ – S phase

Ans. is ‘a’, ‘b’ & ‘c’ i.e. HER2/neu, P53 & BRCA1