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备份 p32 p53 癌 Warburg effect 癌组织研究中的非线性思维

已有 5160 次阅读 2012-5-24 17:48 |系统分类:科研笔记| cancer, p53, mitochondria, p32

坑爹的ResearchGate,把博客功能删了。趁着还能看到原来的博文,赶紧转过来做个备份。下面这一篇大概是两年前写的。具体时间也找不到了。还在愤怒中……

本文起了个故弄玄虚的标题,却没多少吸引眼球的作用。主要就是讲两个蛋白质,p32 和 p53, 它们在癌细胞中的过量表达,对于氧化呼吸的恢复有相似的作用,但最终造成的结果却完全相反。在癌细胞中,经常会发现线粒体的氧化呼吸功能收到抑制或者损坏,称为Warburg 效应。通过人为诱导表达某些处于氧化呼吸链上的蛋白(亚基),能够恢复线粒体的氧化呼吸功能。p32 和p53就是这样的两个蛋白。奇怪的是,过量表达p53能抑制癌细胞生长,过量表达p32却能促进癌细胞生长。本文就是简要地介绍了这一表面看来的矛盾。

当然你可以说,由于这些实验是基于不同的癌症类型、不同的人群,所以背后的原因也肯定与这些不同的背景因素有关。我不否认这样的说法。但是在我的眼里,这样表面上相互矛盾的结果,显然反映了背后有比较复杂的、非线性的规律。如果能从系统性的思维里找到备选答案,并且能够设计实验来验证答案,那将是很有意义的事情。

本文也顺带提到了过去十年内部分科学家试图从种群遗传、进化博弈等角度来研究癌组织的一些思路。我个人认为这些思路都很有价值,但是有很多缺陷,需要后来人进一步敲打。

标题:p32 & p53, twins with different fates

Fogal et al (2010) found that the p32 gene (on human chromosome 17q13.3), which was overexpressed in some cancer cells, had actually promoted the level of oxidative phosphorylation (OXPHOS) in mitochondria. The knockdown of p32 in an experiment then lead to a lower level of complexes III, IV and V composing the electron transport chain (ETC) of OXPHOS, thus making a shift in ATP synthesis from OXPHOS to glycolysis in tumor cells, but meanwhile causing a lower level of tumor growth than before. 

This is contradictory with the well known Warburg Effect (Warburg 1924), i.e. an elevated level of glycolysis and glucose consumption as a hallmark of tumor growth, hypothesized to provide a growth advantage for the tumor cells.

However, another gene p53 (on human chromosome 17p13.1), also promoting OXPHOS, is a well known tumor suppressor. p53 could inhance expression of Cytochrome c Oxidase II (also a part of complex IV of ETC), which is essential for OXPHOS in mitochondria. p53 is found to have mutated in many cancer cells, causing a shift from OXPHOS to glycolysis (Matoba 2006) during tumor growth. This is in turn consistent with Warburg Effect.

As the result we see two genes located on the same chromosome regulating the balance between OXPHOS and glycolysis in the same way. However, they seem to play opposite roles in carcinogenesis. So why are they so different?

One possible reason may lie in their roles in inducing apoptosis. Over-expression of p32 could induce apoptosis only when p53 functions in normal status (Itahana & Zhang 2008). So once p53 is disfunctional in cancer cells as said above, the overexpression of p32 won't cause apoptosis alone, and thus won't give any disadvantage against the tumor cells. On the other hand, overexpression of p32 could produce ATPs for tumor cells in a higher efficiency. In such a hypothesis p32 would not be an oncogene, but is only overexpressed as a consequence of carcinogenesis. And in such a case, the Warburg Effect is not rejected but irrelevant to the mechanisms here.

Anyway, the Warburg Effect has been questioned more than once (Weinhouse et al 1956; Zu & Guppy 2004; Dang 2010). Although the inhibition of OXPHOS and promotion of glycolysis have been correlated to carcinogenesis either as a cause or as a consequence in numerous studies throughout the last 80 years (too many literatures), the underlying mechanisms seem still unsolved. And it is still possible to answer the above question in the context of metabolism regulation based on the framework raised by Warburg.

Many studies have been proposing an evolutionary perspective onto the correlation between ATP synthesis and carcinogenesis (e.g. Gatenby & Vincent 2003; Pfeiffer & Schuster 2005; Vincent 2006), by considering the tumor/normal cells within the same tissue/organ as a population, in which individual cells compete with each other in a series of cell generations within the life span of the human body. Such a micro-evolution process could be investigated with methods from population genetics, adaptation dynamics, theories of competition and coexistence, etc. These Darwinist have provided interesting viewpoints and they never forgot about the important roles of mitochondrial functions and mtDNA mutations in tumor growth. However, they seldom considered the cooperation between the mitochondrial genome and the nuclear genome, as de Bivort et al (2007) did in their effort to correlate such an coevolutionary force behind ATP synthesis with the progression of some mitochondrial diseases.

It is known that many proteins and enzymes involved in mitochondrial functions, including complexes I, III, IV and V of the ETC, are composed of both mtDNA-encoded and nDNA-encoded subunits (Wallace 2005). Interestingly, both p32 and p53 could regulate complex IV, but not complex II, which is encoded solely by nDNA. Considering that the two genomes belong to different hierarchies of life forms, some delicate cooperation mechanisms may have evolved to keep them match in a cell. Such mechanisms could be vulnerable to novel influences in the modern world, either environmental or physical, causing cyto-nuclear conflict. It is worth including such cyto-nuclear mismatch/incompatibility patterns when constructing an evolutionary model to answer the above question.

Vital references

  • Fogal, V., Richardson, A. D., Karmali, P. P., Scheffler, I. E., Smith, J. W., & Ruoslahti, E. 2010. Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Molecular and Cellular Biology 30: 1303-1318.
  • Matoba, S., Kang, J., Patino, W. D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P. J., Bunz, F., & Hwang, P. M. 2006. p53 regulates mitochondrial respiration. Science 312: 1650-1653.
  • de Bivort, B. L., Chen, C., Perretti, F., Negro, G., Philip, T. M., & Bar-Yam, Y. 2007. Metabolic implications for the mechanism of mitochondrial endosymbiosis and human hereditary disorders. Journal of Theoretical Biology 248: 26-36.


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