Background: Human papillomavirus (HPV) is the etiological agent for multiple for
ID: 3165474 • Letter: B
Question
Background:
Human papillomavirus (HPV) is the etiological agent for multiple forms of cancer, including cervical, oropharyngeal, penile and anal cancers. Of these, HPV-mediated cervical cancer is the most common. Primary HPV infection occurs in undifferentiated columnar cells of the cervical basal epithelium, the endocervix. Conversely, virions egress exclusively from terminally differentiated cells comprising the outer layer of the cervical epithelium, the ectocervix. Thus, the virus relies on proliferation and subsequent differentiation of endodermal cells up the cervical epithelial wall for the production of new virions. To ensure this process occurs, HPV encodes two proteins, E6 & E7, to inhibit apoptotic pathways and promote cellular proliferation, respectively. E6 binds to and inactivates p53 while E7 binds to and inactivates retinoblastoma protein. In over 80% of HPV-mediated cervical carcinomas, the viral genome integrates into the host genome. Ultimately, this causes unregulated production of oncoproteins E6 & E7 and cancer arises as a result of this overexpression.
In the first part of the assignment (TH2) you focused on deregulation of cell cycles via E7. In the second part of this assignment, your primary focus will be on deregulation of cellular DNA repair/apoptotic pathways.
1) HPV protein E6 binds to and inactivates p53.
a) What is the normal cellular role of p53 in the DNA damage response? (include downstream effector(s) of p53 in your answer)
b) How is p53 normally regulated in the cell (i.e. what turns it off/on)?
c) Classify p53 as a tumor suppressor or a proto-oncogene?
d) What would be the result of p53 inactivation with respect to the cell cycle?
e) P53 not only has a role in the DNA damage response but also in the intrinsic apoptotic pathway. Explain how p53 can promote activation of the intrinsic apoptotic pathway.
Explanation / Answer
a.
p53 mediate the response of DNA damage by regulating the expression of genes which are implicated in the cell cycle arrest, programmed cell death, senescence and metabolism. A novel transcriptional target of p53 is ACER2 (human alkaline ceramidase 2). The moderate level expression of p53 upregulate the ACER2 that inhibit the cell cycle arrest and cellular senescence. The downstream effector of p53 is also the ACER2.
b.
The regulation of p53 is controlled by the expression of Mdm2 protein. The binding of p53 by Mdm2 can trigger the degradation f p53 through the ubiquitin system. Phosphorylation of p53 at Ser15, Thr18 or Ser20 will disrupt its binding with Mdm2. In normal cells, these three residues are not phosphorylated, and p53 is maintained at low level by Mdm2.
c.
Proto-oncogenes are the genes that normally help cells grow.When a proto-oncogene mutates or there are too many copies of it, it becomes a "bad" gene that can become permanently turned on or activated when it is not supposed to be. Tumor -supressor genes are normal genes that slow down cell division ,repair DNA mistakes,or tell cells when to die,when tumor supressor genes don't work properly ,cells can go out of control,which can lead to cancer. Tumor suppressor genes regulate cellular differentiation and suppression of proliferation. p53 is a tumor suppressor gene as its expression regulate the cell cycles.
Related Questions
Navigate
Integrity-first tutoring: explanations and feedback only — we do not complete graded work. Learn more.