Dear Safiulla,

I see many have already provided great posts. However, I feel perhaps the main point of your question remains to be answered, which asks how highly proliferative cells (under hypoxic conditions) can sustain such activity given their inability to rely on OXPHOS.

This is a very good question that has been given increasing attention in the past few years. Many now posit that, contrary to popular belief, highly proliferative cells actually don't need as much ATP as one would assume. Why? Remember these highly proliferative cells are in a much more de-differentiated state. A proliferating cell is not performing the normal physiological functions of a differentiated cell acting within a tissue - functions which generally depend on OXPHOS. Instead, proliferating cells are tasked with multiplying themselves and their more basic cellular structures. Glycolysis can provide ATP they need, but proliferating cells also heavily rely on the taking up of macromolecules which they can then use to synthesize many of its components.

In short, it is suggested that the energetic needs (referring strictly to ATP) are not as demanding for a proliferating cell as it would be for a differentiated cell performing daily functions. Instead, it has other needs (taking up macromolecules) which it fulfills through its reliance on alternative molecular pathways, such as c-myc, which is of course intimately tied to the HIF-1a pathway, and both of which have an antagonistic relationship to p53 (which pushes for OXPHOS).

Our cells are perfectly equipped to survive in hypoxia, but this is always contextual. Differentiated cells can only do so for some time, but dedifferentiated cells don't rely on oxygen as much to perform their main objective: multiplication (this also puts into question our use of anti-angiogenic drugs).

For example, early stages of embryogenesis are actually quite hypoxic. There are also many "niches" within the adult body that are hypoxic in which stem cells reside perfectly content.

Lastly, I feel its important to mention that I use "differentiated" and "de-differentiated" loosely here. Our current language for describing such states is still rather rudimentary. This is always context dependent... and this applies pretty much to everything discussed in this thread too.

This is all a very interesting topic which we've only skimmed the surface of, but I hope this helps!

This question had been asked during my exam. i didnt get the answer any where. so please help me out to solve this problem.

hi safiullah,

the reason could be cross talk between RAS and RHO signalling pathway. . in a transformed or an oncogenic cell when Ras is activated it activates RhoA GTP which inhibits the cell cycle ihibitor p21/WAF1.. So maybe because of this even with unmutated p53 activity the cell continues proliferation.

i hope this info helps u. any contradiction is welcomed coz i am a student here to learn.

I believe even if the p53 is normal but there is a mutation in other genes that regulate its function, the outcome will be cell division of transformed cell.In normal condition p53 remains as a complex with Mdm2.In transformed cell or cell that has encountered DNA damage,the p53 gets phosphorylated so it can no longer bind to Mdm2.But if there is a mutation in Mdm2 gene that allows the phosphorylated p53 to remain attached to it,then the outcome will be division of that transformed cell.Secondly if there is a mutation in the gene coding for Pin1 protein that actually transform the p53 after its separation from Mdm2, then the Mdm2 freed p53 can no longer undergo the required conformational changes that are required for it to bind to the DNA . So This p53 can no longer stop cell division or signal for apoptosis.So I believe even if the p53 is normal, the other genes which are actually required for its normal functioning are mutated,then also the outcome will be cell divion of the transformed cell.....

hi, its not only p53 that is important, it could be because of other genes that work in combination or with their independent effect.....

Exactly,cell division,cell functioning or any other cellular activity is not governed by a single gene or protein,rather its a collective effect of several molecular activity.So even if p53 is normal,there can be division of transformed cell if there is a change in the basic framework of the other genes involved.

P53 is normal, but transformed cell can divide due to the presence of oncogenes....

Thanks to one and all....

Wel come

Its really amazing to know that a Tumor Suppressor gene can actually act as a Tumor Inducer in case of certain mutation.Really some of the secrets at molecular level are really great and unexpected when they are unfold...

@ paul hill: i have a doubt.. proliferating cells need more amount of energy compared to normal cells and the synthesis of ATP(energy) takes place when the o2 is reduced during the oxidative phosphorylation.my question is during hypoxia where the level of o2 is very low so ATP synthesis is also low then how a cell manages to proliferate in such low energy environment ....

P53 different fold means, induce same mutation in the p53 gene, the new mutated p53 may not inhibit cell divison.,and hence support or induce cell divison may lead to cancer.

Hi Safiulla! :)

Answering to your question, I might say that: usually, tumor cells get their energy becoming glicolitic, meaning that they will decrease the levels of glicose by degrading it. When you have an environment poor in oxygen, there'll be the release of HIF, wich is a protein related with hypoxia conditions. This protein will induce de translation of VEGF, a growth factor related with angiogenesis. This process will be central, because it will be one of the major factor for the tumor growth.

I don't know if I was clear enough for make you understand! Any further doubt please ask :)

Kind regards.

* to make you understand

Hypoxia induces angiogenesis.This can be explained,depleted oxygen condition in cell,for want of oxygen(survival adoption), produce a protein, in such a way that ,the protein induces angiogenesis.

Thanks Mariana.. I understood.

Dear Safiulla,

I see many have already provided great posts. However, I feel perhaps the main point of your question remains to be answered, which asks how highly proliferative cells (under hypoxic conditions) can sustain such activity given their inability to rely on OXPHOS.

This is a very good question that has been given increasing attention in the past few years. Many now posit that, contrary to popular belief, highly proliferative cells actually don't need as much ATP as one would assume. Why? Remember these highly proliferative cells are in a much more de-differentiated state. A proliferating cell is not performing the normal physiological functions of a differentiated cell acting within a tissue - functions which generally depend on OXPHOS. Instead, proliferating cells are tasked with multiplying themselves and their more basic cellular structures. Glycolysis can provide ATP they need, but proliferating cells also heavily rely on the taking up of macromolecules which they can then use to synthesize many of its components.

In short, it is suggested that the energetic needs (referring strictly to ATP) are not as demanding for a proliferating cell as it would be for a differentiated cell performing daily functions. Instead, it has other needs (taking up macromolecules) which it fulfills through its reliance on alternative molecular pathways, such as c-myc, which is of course intimately tied to the HIF-1a pathway, and both of which have an antagonistic relationship to p53 (which pushes for OXPHOS).

Our cells are perfectly equipped to survive in hypoxia, but this is always contextual. Differentiated cells can only do so for some time, but dedifferentiated cells don't rely on oxygen as much to perform their main objective: multiplication (this also puts into question our use of anti-angiogenic drugs).

For example, early stages of embryogenesis are actually quite hypoxic. There are also many "niches" within the adult body that are hypoxic in which stem cells reside perfectly content.

Lastly, I feel its important to mention that I use "differentiated" and "de-differentiated" loosely here. Our current language for describing such states is still rather rudimentary. This is always context dependent... and this applies pretty much to everything discussed in this thread too.

This is all a very interesting topic which we've only skimmed the surface of, but I hope this helps!

Thanks to one and all for providing such an important information.

dear safiulla

at first we have normal tissue then if by any chenges we had overexpression in for example RAS it could lead to adenomatose and then in the next step loss of P53 will lead to malignancy but meanwhile without loss of p53 if we had overexpression of some ancogenic Mir like mir17 family it could promote cell devision or loss of mirs wich are tummor supressor genes could do the same in adition you could serch the crole of p73 and p63 as well

p53 is degraded via ubiquitin pathway and it is triggered by mdm-2. Anything which interacts with this degredation may shorten p53 half-life and thus decreases its biological function as in HPV infection where E6-E6AP replaces mdm-2 and shortens p53 half-life

Dear all,

For those interested in reading more about what I discussed, I recommend the following review:

http://www.sciencemag.org/content/324/5930/1029.short

Can I suggest a term for you to look into, regarding the energy required for proliferating cells?

The Warburg Effect.

Not sure how much it might help, no harm trying.

Safiulla, a transformed cell is a cell that has lost normal p53 activity. Therefore with a dysfunctional p53, cell division and other cell activities are unregulated and unrestricted.

P53 has been shown to be degraded by the UPS system, it could be that p53 has its normal activity but not its respective ubiquitination, meaning that, in your specific transformed cell(s), p53 is being excessively degraded, leaving cells with low levels of necessary protein to halt the cell cycle.

and it could be that with a degraded, non-ubiquitinated p53 (and with the transformed cell not going into apoptosis); the transformed cell still can maintain its abnormal activity because the NK cells are unable to recognize this abnormal phenomenon.

You can also get lesions in other pathways downsteram of p53 that render P53 irrelevant. For Burkitt lymphoma, if you lose expression of the pro-apoptotic protein Bim and p16INK4A (part of CDKN2A locus) then that seems that you can develop tumours with wild-type p53, that responds appropriately to stimulation. I suspect that this applies to other cell types as well, and/or similar mutation combinations can substitute for wild-type p53 in other cell types.

The answer to your question lies in your question stem. You write "we all know that p53 will inhibit the cell to undergo cell division", and this is true but a more complete treatment would be to say that the p53 pathway will inhibit cell division. By taking this global view you quickly realize that if you have normal p53 activity and simultaneous loss of integrity along the pathway the cell can proliferate. Yes p53, as the hub is important but so too is its program of downstream genes.

I agree with Wayne Warner's answer. Because of these reasons some researchers say that p53 has dual face. Though p53 function as regulatory protein for cell cycle, but in some instances/conditions it function as a pro-oncogene regardless of its mutation status.