Howard Temin Research Articles

Howard Temin memorial lectureship. Molecular biology of HTLV-1: deregulation of host cell gene expression and cell cycle.

Tax, a regulatory protein of HTLV-1, is an oncoprotein which immortalizes human T-cells and induces tumors in transgenic mice. Here, we found that Tax binds to a cyclin-dependent kinase inhibitor, p16Ink4a. p16Ink4a binds to cyclin-dependent kinases, CDK4 and CDK6, and inhibits their activity, resulting in suppression of G1 phase progression. The binding of Tax to p16Ink4a induced a reduction of p16Ink4a/CDK4 complex, with subsequent activation of CDK4 kinase. Tax also suppressed p16Ink4a-mediated inhibition of cell growth. The p16Ink4a gene was frequently deleted in many T-cell lines, but not in HTLV-1-infected T-cell lines. Taking these findings together, the functional inactivation of p16Ink4a by Tax through protein-protein interaction is suggested to contribute to cellular immortalization and transformation by HTLV-1.

Recollections of Howard Temin (1934-1994).

Recollections of Howard Temin (1934-1994).

Error-prone retrotransposition: rime of the ancient mutators.

In 1964, Howard Temin (1) first proposed that genetic information might actually flow in reverse (i.e. from RNA to DNA) in some organisms. The subsequent codiscovery of RNAdependent DNA polymerases (reverse transcriptases) by Temin and Mizutani (2) and Baltimore (3) solidified this revolutionary idea and provided a key to the identification of a large group of evolutionarily related mobile genetic elements that encode their own reverse transcriptases and replicate through RNA intermediates (DNA -> RNA -> DNA; 4-6). These exist across broad phylogenetic boundaries (bacteria, algae, plants, fungi, insects, birds, fish, and mammals) and include bacterial episomal elements (msDNA), mitochondrial retroplasmids and group II introns, interspersed repeated sequences [long terminal repeat (LTR) retrotransposons and non-LTR long interspersed nuclear elements (LINE)-like elements], and replicating viruses (retroviruses, hepadnaviruses, and caulimoviruses). Comparisons of genome organizations, replication mechanisms, and reverse transcriptase sequences and functions clearly point to evolutionary relationships among retroelements (6-9). Although the temporal order of retroelement evolution is controversial (6), it has been suggested that retroelements were evolutionary links between ancient RNA and DNA worlds (10). A hallmark of retroelements is their genetic heterogeneity. This was discovered first (11) and is best documented (12-15) for retroviruses that have been shown to exist as complex mixtures of genetically heterogeneous virions (quasispecies) that are ever-changing. Studies of nonviral retrotransposons and mitochondrial retroplasmids suggest that genetic variation is also a property of other retroelements (16-23; GenBank data base). The frequency of genetic variants within a population of retroelements may be influenced by many factors, including mutation rate, the number of retrotransposition cycles, selection, population size, competition, and random sampling (24). The distinction between mutation frequency (i.e., the proportion of mutants in a population at any given time) and mutation rate (i.e., the number of de novo mutations arising per nucleotide per cycle of replication) is very important if one is to understand underlying mechanisms of genetic variation (25). Recent studies using recombinant and clonally purified retroviruses have permitted the quantitation of mutation rates after a single cycle of replication in the absence of strong selection (reviewed in ref. 15). These studies show that retroviruses, like other RNA viruses, mutate at very high rates (0.05-1 mutation per genome per replication cycle), resulting in base substitutions, frameshifts, genetic rearrangements, and hypermutations. Although it has long been suspected that other retroelements also mutate at high rates (16, 17), technical difficulties have precluded a rigorous quantitation of these rates.

The Pastorian: A Legacy of Louis Pasteur

Publisher Summary This chapter focuses on the researches carried out by Andre Lwoff in the field of lysogeny and describes the way his work inspired Howard Temin and other scientists to understand retroviruses, and thus prepared the world to identify the cause of acquired immunodeficiency syndrome (AIDS). It mentions two experiments undertaken by Lwoff to extend the Wollmans' hypothesis—bacteriophages contained genetic instructions and—such instructions were inherited by lysogenic bacteria. The findings, coupled with the growing recognition that genetic information resides in DNA, permitted Lwoff to propose a simple and prophetic explanation of lysogeny. According to him, viral infection can either result in the massive production of new viruses and destruction of the bacterium or can lead to the perpetuation of the bacteriophage's genes inserted into the chromosome of the bacterium in an inactive form called a “prophage.” Howard Temin proposed ways in which the infection of an animal cell by a retrovirus resembled the establishment of the lysogenic state in bacteria. His highly unorthodox proposal that viral genes are converted from RNA to DNA during infection, stimulated him to seek and to find an enzyme capable of copying RNA to make DNA. This enzyme, now known as reverse transcriptase, is a distinctive component of all retroviruses and of a few other viruses; an important factor in current views of early evolution; an essential tool in the biotechnology industry; a sign by which human immunodeficiency virus (HIV), the AIDS virus, was detected and recognized as a retrovirus; and the target for the only drugs widely used against HIV.

Discovery of the reverse transcriptase.

1995 is the 20th anniversity of the award of the Nobel Prize in Physiology or Medicine to David Baltimore and Howard Temin for the discovery of the reverse transcriptase. The prize was shared with Renato Dulbecco.

Howard M. Temin - 10 December 1934--9 February 1994.

Howard M. Temin died on 9 February 1994, at the age 59. He was awarded the Nobel Prize in 1975 for the discovery of a new mechanism of genome reproduction, called ‘reverse transcription’. Transcription is the term used to identify the transfer of information from genes made of DNA to their messengers, which are made of RNA. The messengers then transfer the information to the proteins, which express the information of the genes. In reverse transcription, on the contrary, the information is transferred from RNA to DNA as part of a reproductive cycle. Howard Temin (and independently David Baltimore) discovered the new mechanism by studying a class of viruses that cause leukemias or cancer in a variety of animals. The discovery was sensational because at that time biologists had become used to the idea that information is transferred from DNA to RNA and not vice versa. As often happens, this was considered a ‘central dogma of molecular biology’. However, the only reason for accepting the dogma was that nobody had shown that it could happen the other way. Nevertheless, the breaking of the dogma by Temin and Baltimore had a very strong resonance.

Thinking about Howard Temin.

Thinking about Howard Temin.

National Cancer Advisory Board Honors Howard Temin for "Life and Work and Courage"

National Cancer Advisory Board Honors Howard Temin for "Life and Work and Courage"

RNA Tumor Viruses

To the Editor.— The prodigious discovery of reverse transcriptase (the enzyme that codes for the production of DNA off an RNA template) represents a milestone in the annals of molecular biology. As such, I would like to call attention to an erroneous paragraph that appeared in a recent article in the MEDICAL NEWS section ofThe Journal(231:335, 1975). The original observation of the presence of reverse transcriptase in RNA tumor viruses was reported independently but concomitantly by Howard Temin and Satoshi Mizutani of the University of Wisconsin and by David Baltimore of the Massachusetts Institute of Technology. Both reports were published in a single issue of Nature in June 1970. 1,2 In addition, Temin and his colleagues conducted their investigations at the McArdle Laboratory for Cancer Research in Madison, Wis, not at the National Institutes of Health. Third, and least importantly, Howard Temin holds a PhD, not an MD,

Viral Etiology of Cancer: Two Hypotheses With Relevance to Chemical Exposures

In discussing the area of cell biology in relation to the topic of Dr. Fraumeni's presentation and in relation to the Conference as a whole, I decided to describe two current hypotheses of carcinogenesis-first, the viral oncogene hypothesis proposed by Drs. Huebner and Todaro and, second, the protovirus hypothesis proposed by Dr. Howard Temin. These two hypotheses tend to reconcile the position of the two schools of thought about cancer etiology, namely, the environmentalists and the virologists. Both hypotheses are derived from observations of the RNA tumor viruses, namely, type B virus associated with mammary tumors in mice and the type C viruses associated with leukemia, lymphoma, and sarcoma in a number of animals; with autoimmune diseases in mice; and with a neurologic disease of mice. VIRAL ONCOGENE HYPOTHESIS This hypothesis, proposed first by Huebner and Todaro,1 is similar to that stated by Payne and Chubb2 and by Bentvelzen and Daams.3 The hypothesis states that most or all vertebrates contain the genetic information for producing a type C RNA virus in their somatic as well as in their germ cells. This information has been part of the genetic makeup of vertebrates since early in evolution and can persist for many generations in cell culture without overt production of virus. The virogenes (genes for production of type C viruses) and the oncogenes (that portion of the virogene responsible for transforming a normal cell into a tumor cell) are maintained in unexpressed form by repressors in normal cells. Various agents, including physical and chemical carcinogens, may transform cells by switching on the endogenous oncogenic information.