Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.

Now try this multiple-choice quiz:

In the 3.5 years between January 1993 and July 1996, how many research papers have been published in which the term "p53" appears in the title? (a) 43; (b) 430; (c) 4,300; (d) 43,000.

Readers who guessed (c) are winners.

The p53 protein has a molecular weight of 53 Daltons (hence its numeric name). Its gene resides on the short arm of human chromosome 17, whence it encodes the p53 protein, commonly regarded as the most potent and versatile "guardian" of the mammalian genome. In fact, p53 holds two contrarian titles: key tumor suppressor and - when mutated - macho tumor promoter. Almost half of all human malignancies contain a p53 mutation. These include cancers of the breast, cervix, colon, lung, liver, prostate, bladder and skin - to cite the most aggressive and lethal.

A team of scientists at the Johns Hopkins Oncology Center in Baltimore tracked the elusive p53 all the way down chromosome 17 in 1989. Then, when they examined tumors from 56 patients, their noncancerous cells had two normal p53 copies. But three-fourths of the same patients' tumors harbored just one copy of p53, which was somewhat mutated at that. When they reported this finding in April 1989, the p53 oncogene-cum-tumor suppressor came fully of age, worldwide.

Many cancer chemotherapies and radiotherapies kill tumors by triggering apoptosis - programmed cell death - against them. But in cancers where p53 is mutant, these therapies are greatly weakened.

Some damaged cells can be fixed, but others have to die. It's a longstanding oncological puzzle how the tumor suppressor p53 determines the cell's fate, depending on the damage done. The issue of Nature, dated April 3, 2003, reports that the phosphatase enzyme PAC1 is necessary and sufficient to induce p53-dependent cell death. The paper is titled "PAC1 phosphatase is a transcription target of p53 in signaling apoptosis and growth suppression." Its authors are at Columbia University College of Physicians & Surgeons, Department of Radiation Oncology.

PAC1 is activated only by stress that results in the cell's demise - for example, oxidative damage - but not in response to gamma-irradiation, an anticancer treatment that causes arrest of cell-cycle division. The co-authors derived a cell line from a human colon cancer with mutant p53. These cells underwent apoptosis after serum deprivation in the presence of p53, which greatly increased PAC1 expression.

Unexpectedly, p53 activates the transcription of PAC1 in a rather unusual manner: It binds a "palindromic" site in the PAC1 promoter rather than the customary "consensus" p53 binding site.

In common usage, a palindrome is a series of letters, words or phrases that read the same forward and backward. Thus, in Biblical legend, when Adam first woke up in the Garden of Eden, he greeted Eve palindromically - "Madam, I'm Adam."

Genomically, a palindrome is a symmetrical, repeated sequence in DNA molecules such that the sequences in the two strands are the same if read in the same polarity. An example cited in the Nature paper: "During apoptosis, p53 activates transcription of PAC1 by binding to a palindromic' site in the PAC1 promoter, rather than the consensus' p53-binding site. Identification of a palindromic motif as a p53-binding site may reveal a novel mechanism whereby p53 regulates its target genes." The palindrome was illustrated in the Nature paper as 10 two-way nucleotides.

"We demonstrate here," the article concluded, "that p53 uses a palindromic binding site to regulate its target gene PAC1. Thus it is conceivable that p53 may selectively regulate different groups of target genes through this mechanism. Its identification will provide insights into the molecular basis of how p53 selectively regulates its target genes to eliminate cancer cells and suppress tumorigenesis."

New Twin Studies, Genetic Linkage Analysis, Synapse Scrutiny Seek New Light On Autism

"Failure to cuddle" is one of the many formal definitions of autism - an affliction of children (and their parents). Its onset is usually before the age of 3, and its prognosis is grim if useful language isn't mastered by age 7. Autistic boys outnumber girls by four to one, for reasons nobody knows.

An article in the current issue of Nature Genetics, released online March 31, 2003, bears the title "Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism." Its authors are at the University of Paris, Laboratoire de Génétique Humaine et Fonctions Cognitives.

"Many studies," their article leads off, "have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism."

The authors define the childhood psychosis as "impaired reciprocal social interaction and communication," plus "restricted and stereotyped patterns of interests and activities." They add, "The recurrence risk of autism in siblings is approximately 45 times greater than in the general population, and twin studies have documented a higher concordance rate in monozygotic [identical] (60-90 percent) than in dizogotic [fraternal] twins (0-6 percent)."

The paper notes, "At least two loci on the X chromosome have been suggested to be associated with a predisposition to autism."

The authors screened for neuroligin mutations in 36 pairs of affected siblings and 122 trios. Their paper concludes: "Three independent lines of evidence strongly suggest that mutations in NLGN3 and NLGN4 are involved in autistic-spectrum disorders. First, deletions at the short arm of chromosome X have been reported in several autistic individuals. Second, the point mutations in NLGN3 and 4 cause severe alterations of the predicted protein structure. Third, a mutation in NLGN4 appeared de novo in one affected individual's mother."

They hypothesize in conclusion that "a defect in NLGN 3 or 4 may abolish formation, stabilization or recognition of specific synapses essential for the communication processes that are deficient in individuals with autistic spectrum disorder."

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