Retroviral Promoters and Cancer, One Example

Being a young scientist, I take a lot of ‘science’ for granted. Weve ‘always’ had PCR. Weve ‘always’ had restriction enzymes. We ‘always’ knew HIV-1 is a retrovirus, and uses CD4 and CCR5/CXCR4 to infect cells. Weve ‘always’ known that retroviruses are important for the evolution of life on this planet. We ‘always’ knew about micro-RNA and the RNA silencing machinery.

So its wonderful fun to read papers written before we knew X, Y, Z– watching the discoveries take place. Considering my last entry was about how much you totally dont want ERVs to be functional, I thought Id write about a real world example about how retroviral promoters can be an ‘alternate’ promoter for a ‘normal’ gene, and end up causing cancer.

A long time ago, in the before times, a group was studying how infection with Avian Leukosis Virus lead to cancer. ALV is a bird retrovirus that comes in both endogenous and exogenous flavors, which has actually caused a lot of trouble in the past (endogenous ALV rearranging with exogenous ALV lead to a really bad ALV epidemic in the 1990s).

They found that ALV really liked to insert upstream of a gene they called ‘bic’ (B cell Integration Cluster, bic). When B-cells were infected with ALV, the retroviral promoter acted as an alternate promoter for bic, and bic was way, way upregulated in cancerous cells. They looked in lots of different b-cell lymphomas, and they found the same thing– an ALV insertion somewhere upstream of bic, lots of bic.

So they played around with the bic transcripts, figuring they had discovered a new oncogene… but they noticed something odd… The bic RNA didnt code for a protein. There werent any open reading frames.

In this paper, it was awesome to see the researchers reason this out. Bic is processed, but no gene. Is it a pseudogene? Hmm, no, doesnt have the genetic characteristics of a pseudogene. And its super cell specific, no way is it a pseudogene. Maybe with ribosomal frame-shifts, theres something there? No, too many stop codons. Maybe it just works as an RNA? The secondary structure is really complex– Maybe the RNA does something on its own?

Bam. They were right. They didnt know about microRNA yet, but they found one, and made the right conclusions. I love reading stuff like this in old papers :)

Comments

  1. #1 Bob O'H
    August 27, 2008

    There. We oldies aren’t always so stupid.

  2. #2 Brian
    August 27, 2008

    I also notice that older papers tend to be less formal, and easier, even, dare I say, FUN to read.

  3. #3 Cairnarvon
    August 27, 2008

    I really enjoyed Erwin Schrödinger’s What is Life?, which was published in 1944, for much the same reasons, though it’s not a paper and it’s a bit more accessible to laypeople.
    Reading about DNA as the carrier of genetic material in the hypothetical was interesting.

  4. #4 Cath@VWXYNot?
    August 27, 2008

    Great stuff! This kind of brings together my PhD thesis research (the v-Jun gene, a copy of the avian c-Jun gene that got picked up by a retrovirus and mutated to the point that it causes sarcomas when reintroduced into avian cells by viral infection) and my postdoctoral research (endogenous retroviral promoters and how they affect human gene expression).

  5. #5 Doc Bill
    August 27, 2008

    I did my Masters on using pattern recognition of GC-MS data to identify dipeptides. We didn’t have a complete set of all dipeptide combinations so the idea was to use pattern recognition to determine if a particular amino acid was on the amino or carboxyl end of the pair. Then, using peptidiase (?), an enzyme that chopped proteins into dipeptides, we could use a computer do put together the sequence.

    I wrote initial pattern recognition programs (learning machine and k-nearest neighbor) in FORTRAN. It was months of work to just generate the raw data.

    Result? Inconclusive.

    Those were the days!

    Now, to see DNA sequenced in a matter of days is nothing short of magic. Yes, it’s a miracle!

  6. #6 Jared
    August 28, 2008

    Those pesky CXCs, always getting into trouble…

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