How HEXIM1 stops the spread of cancer - Part 1.

Thank you all for your support so far! With a little less than two weeks to go we are 1/3 of the way to our target of $7000 to test new drugs which induce HEXIM1. Which of course raises the question of why inducing HEXIM1 is so good at stopping the spread of cancer (metastasis). First lets consider what cancer represents in a biological sense.

Mammalian organisms exert a high degree of control over the timing and location of cell division and growth. Obviously during embryogenesis there is a carefully programmed pattern of cell growth, proliferation and anatomical development to form limbs, organs and tissues etc. However once these processes have been completed, it is important to shut off the continued growth and development of the vast majority of cells in the body.

Most of the genes involved in growth and proliferation are expressed by the action of RNA Pol II polymerase, which itself requires a factor P-TEFb (Positive Transcription Elongation Factor) to make full length gene transcripts from target genes. P-TEFb is found in the cell in a ratio between a free form which is able to assist RNA Pol II and a reversibly sequestered form bound to a complex called 7SK snRNP.

 

source: http://en.wikipedia.org/wiki/P-TEFb / Drawing by David H. Price  Copyright CC BY-SA 3.0

As you can see, HEXIM1 is also a component of 7SK snRNP and recruits P-TEFb to the complex. Consequently higher levels of HEXIM1 protein in a cell shift the ratio of P-TEFb away from the free form which promotes RNA Pol II elongation, towards the inactive form which is bound to the 7SK snRNP complex. In this way, progrowth / proliferative genes are negatively regulated by high levels of HEXIM1. In cancer, this balance has been lost (for a variety of reasons which we will discuss in another lab note) and expression of progrowth / proliferative genes leads to tumor formation and progression.

Our approach to stop the spread of cancer by inducing HEXIM1 is so powerful because essentially all of the RNA Pol II dependent genes can be turned down or turned off completely through the induction of higher levels of HEXIM1 protein with our new drugs.

Now HEXIM1 also acts against cancer by some P-TEFb independent mechanisms as well, which will be the topic of Part 2, our next lab note posting.