My thoughts run free here...

Friday, May 5, 2006

Apoptosis and me


Today was a slacky day, deprived of any GP lesson. Wow! I'm so happy. I have used 'happy' so many times. But i really have a lot of worries currently in my mind. My short-term worry is about passing my final-NAPFA test next week. I would be free to follow my own fitness regime after NAPFA. I pray to God everyday that the weather on my 2.4km running-day should be cold and drizzling if possible. Oh pls pls pls God.

Oh well, do i have any choice? I have to run NAPFA. And the chances of me passing depends on my will power and motivation on that day. I should try very hard to run all the way. But i wonder how the ordeal to pass the cheering class of boys for each and every 6 rounds would be like. I would love it if someone runs with me all the way. But i don't want to trouble anyone. I'm better off with me motivating myself.

I was reading an article on apoptosis, which is cell death. Below is the excerpt from the Institute of Cancer Research:

"During early development, apoptosis is needed to sculpt structures such as fingers and toes. Later on in life, apoptosis is also instrumental to ensure that organ size remains constant – a process called tissue homeostasis. For example, during each menstrual cycle the epithelium of the normal human breast undergoes a phase of cell expansion. However, later on, a phase of
cell removal follows which reduces the breast back to its original size. Similarly, during regnancy and lactation high levels of cell proliferation and differentiation occur in the breast, leading to a massive expansion of the mammary gland. But, after lactation has finished, the differentiated lactating lobules are no longer required and are then removed by apoptosis, returning the organ
to its mature resting state. Thus, during adult life, as during development, numerous structures are formed that are later removed by apoptosis."

Very interesting isn't it? Apoptosis plays a very important role in cancer.

"Substantial evidence indicates that the very same genetic mutations that trigger uncontrolled cell expansion, and hence might give rise to cancer, at the same time also trigger spontaneous activation of cell death. The finding that the molecular lesions that generate uncontrolled cell expansion also coordinately trigger cell death indicates that under normal circumstances apoptosis acts as a fail-safe strategy to hinder the expansion of potentially harmful cells. In
this respect, apoptosis acts as part of a quality-control and repair mechanism that eliminates unwanted cells. Consequently, cancer can only ever emerge if apoptosis has been suppressed."

Below is the excerpt about cancer research done on the role of apoptosis in cancer:

"To try to resolve how cancer cells bypass apoptosis, the Apoptosis Team within The Breakthrough Toby Robins Breast Cancer Research Centre is studying the machinery that executes apoptosis and the molecular mechanisms that control this potentially catastrophic
process. Our work concentrates on the engines of the apoptotic execution programme. The destructive components of this cell-death machinery consist of a group of highly specialised proteases (enzymes that break down proteins) called caspases.

Caspases form the molecular chainsaws of the self-destruct programme which, when activated, cut the cell to pieces. Activation of caspases is a key event in apoptotic signalling and is required to execute cell death. Caspases are present in every cell at all times, but remain dormant. However, upon exposure to DNA damage, chemotherapeutic compounds or developmental signals, caspases become rapidly activated. Once active, caspases cleave and destroy a
multitude of polypeptides inside the cell that are vital for cellular function, shape and integrity. Cells are destroyed and removed within minutes of caspase activation – an event which is, self-evidently, potentially catastrophic and must be tightly regulated."

Inhibitors of apoptosis (IAPs) function as guardians of the apoptotic machinery. Recent studies show that several human IAPs are strongly upregulated in many cancers. Since IAPs suppress apoptosis very effectively and are present in cancer cells, tumour pathogenesis occurs. This is also the cause of disease progression and resistance to drug treatments in cancer. Mark Ditzel and Rebecca Wilson have investigated how IAPs suppress cell death. They made the striking
observation that IAPs inhibit deadly caspases by fusing another protein, called ubiquitin, onto caspases. The ubiquitin label inactivates the caspases and the cancer cell survives. IAPs belong to a specialised group of proteins, called E3 ubiquitin protein ligases, which transfer ubiquitin
protein labels onto caspases thereby blocking cell death. It is now clear that apoptosis is implemented by caspases. To date 11 caspases have been identified in humans.While XIAP suppresses only three of these, it is currently unclear how the remaining set of caspases is controlled.

I've also read something very interesting. Read this too:

"Tencho Tenev and Anna Zachariou have studied how caspases are kept in abeyance. They made the discovery that certain caspases carry an evolutionarily conserved motif, which is designed to attract and bind to IAPs, hence the name IAP-binding motif (IBM). Normally, this
IBM is buried deep within a dormant, non-active caspase. However, when the caspase is activated, this motif is exposed and acts like a magnet for IAPs. Thus, even when caspases are activated this will not necessarily end in cell death, because IAPs can home in on active caspases and smother their destructive potential. The most exciting aspect of this discovery is that only a tiny motif, in fact, one single amino acid residue of the caspase, is crucially involved in anchoring it to IAPs. Mutation of this one residue completely abrogates the interaction between IAPs and caspases. Consequently, activated caspases become invisible for IAPs and therefore are unrestrained and free to cause mayhem."

In the future:

Small molecule inhibitors already exist to block IAPs. Future studies will undoubtedly determine whether such SMAC compounds can be turned into efficacious small molecules that enhance the apoptotic mechanism, either alone or in combination with conventional hemotherapeutic agents.

I liked this article. Its taken from the annual research report 2004 from the Institute of Cancer Research website.


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