A Group Of Cells Display Uncontrolled Growth Biology Essay

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Introduction:

Disease in which a group of cells display uncontrolled growth that causes destruction of adjacent tissues and also leads to metastasis

P53:

Protein which is the product of tumor suppressor gene.

Regulates cell growth and proliferation and prevents unrestrained cell division after chromosomal damage, from UV or ionizing radiation.

Absence of p53 as a result of gene mutation increases the risk of developing various cancers.

History of p53:

Identified in 1979 by Arnold Levine at Princeton University, David Lane at Dundas University and William Old at Sloan-Kettering Memorial Hospital.

It was hypothesized to be the target of tumor inducing SV40 virus strain.

It was revealed as a tumor suppressor gene in 1989 by Bert Vogelstein from Johinsd Hopkins School of Medicine.

Gene description:

The name p53 indicates the protein with molecular mass of 53 KDa.

Transformation related protein and a cellular protein which accumulates in the nuclei of cancer cells , binds tightly to SV40 large T antigen.

The gene that encodes p53 was found to have a weak oncogenic activity as the protein over expressed in mouse and human tumor cells.

P53 , widely recognizes as tumor suppressor and p53 gene became probably the common site for genetic alteration in human cancer.

Structure of the gene:

P53 has 393 amino acids and seven domains

N-terminal transcription domain (TAD) , also known as Activation Domain1 (AD1) which activates transcription factors ;residues 1-42.

Activation Domain2 (AD2) which activates transcription factor: residues 43-63.

DNA Binding core Domain (DBD) contains 1 zinc atom and several arginine amino acids; residues 100-300.

Nuclear localization signaling Domain; residues 316-325.

Homo oligomerization Domain (OD) ; residues 301- 355. Tetramerization is essential for the activity of p53.

C-Terminal involved in down regulation of DNA binding of central domain; residues 350- 393.

A tandem of 9-amino acids Trans Activation Domain- 9aaTAD, identified in AD1 and AD 2 region of transcription Factor of p53.

MECHANISM OF WORKING FOR CANCER P53:

In normal cells, the level of p53 protein is low. DNA damage and other stress signals may trigger the increase of p53 protein which has three major functions.

Growth arrest

DNA repair

Apoptosis (cell death)

The growth arrest stops the progression of cell cycle ,preventing replication of damaged DNA.

During the growth arrest,p53 may activate the transcription of protein involved in DNA repair. Apoptosis is the “lost resortâ€Â to avoid proliferation of cells containing abnormal DNA.

The cellular concentration of p53 must be tightly regulated while it can suppress tumors, high level of p53 may accelerate the aging process by excessive apoptosis. The major regulator of p53 is mdm2, which can trigger the degradation of p53 by ubiquitin system.

Several other mechanism of cancer p53 in brief:

It can activate DNA repair proteins when DNA has sustained damage.

It can induce growth arrest by holding the cell cycle at the G1/S regulation point on DNA

Damage Recognition

It can initiate apoptosis, the programmed cell death , if DNA damage proves to be irreparable.

DNA damage

Cell Cycle Abnormalities

P53

P53

Mdm2

Cell Cycle arrest Apoptosis

DNA Repair Death and elimination

of damaged cells

Cell cycle restart

Cellular and Genetic

Stability

In normal cells p53 is inactivated by its negative regulator mdm2. Upon DNA damage or other stress various pathways leads to the dissociation of p53 and mdm2 complex. Once activated p53 will either induce a cell cycle arrest to allow repair and survival of cell or apoptosis to discard the damaged cell.

Significance of mdm2 in mechanism of action of p53:

The levels of p53 are kept low through a continuous degradation of p53. A protein called mdm-2

(Murine double minute 2) also called MDM2 binds to p53 preventing its action and transport it from nucleus to the cytosol. Also MDM acts ubiquitin ligase and covalently attaches ubiquitin to p53 and thus makes p53 for degradation by proteosome. An ubiquitin specific protease, USP 7 cleaves ubiquitin off p53, thereby protecting it from proteosome dependent degradation. Phosphorylation of N-terminal end of p53 disrupts MDM2 binding.

Regulation of P53:

Expression of MDM2 is activated by p53.

Binding of p53 by MDM2 can trigger the degradation of p53 via ubiquitin system.

Phosphorylation of p53 at Ser 15,Thr 18 or Ser 20 will disrupts its binding with MDM2 .In normal cells these three residues are not phosphorylated and p53 maintained at low level by MDM2.

DNA damage may activate protein kinase (such as ATM, DNA-PK or CHK), to phosphorylate p53 at three residues therefore increasing p53 level which also increases MDM2 but has no effect while p53 is phosphorylated. After DNA damage is repaired ,ATM kinase is no longer active and hence p53 will be quickly dephosphorylated and destroyed by accumulated MDM2

Role of p53 in cancer treatment:

Role of p53 and MDM2 in treatment response of Human Germ Cell Tumors.

Adenovirus based p53 gene therapy in ovarian cancer

Clinical studies of p53 in treatment and benefit of breast cancer patients.

Regulation of cancer stem cells by p53.

P53 gene therapy; a potential panacea to cancer.

Trifluorothymidine induces cell death independently of p53.

Clinical significance of p53 alteration in surgically treated prostate cancer.

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